Biology 2A03Lecture 1
Introduction to Physiology&
Homeostasis
Physiological determinates of animal performance1. Vertebrate muscle remodeling
3. Lifetime performance and muscle physiology
2. Regulation of lipid metabolism with environmental stress
4. Toxicogenomics
5. Interactions between oxygen delivery and fuel metabolism
Research in theMcClelland Lab
INSTRUCTORS: Dr. G.B. McClelland – LSB 228
INSTRUCTIONAL ASSISTANT:
Ray Procwat, LSB-215, Ext 24399, [email protected]
LECTURES: Monday, Wednesday, Thursday 13:30 – 14:20, MDCL 1305
LABORATORIES: Monday-Friday – 2:30 - 5:20 pm or 8.30 – 11.20 am; LS/104 or LS/105. Students must attend the lab section to which they have been assigned. Those with conflicts should visit https://scidropadd.mcmaster.ca/dna Changes from assigned sections may be made for reasons of academic conflict only. Documentation of the conflict may be required.
*****Labs start next week – odd # sections 1st week*******
Course Syllabus available on LearnLink
For the rest:Lab handouts will be available on LearnLink or by handout one week before the scheduled lab
Pick up Lab #1 handout in LSB 215
http://www.aw-bc.com/physiologyplace/
****All Quiz and exam questions taken from LECTURE and LAB material
MARKS: 32% 4 Quizzes (written during lecture slots 13:30 – 14:20) Mon. Jan. 23, Mon. Feb. 13, Mon Mar. 13, Mon Mar. 27; Room assignments for quizzes will be announced in class
24% Laboratories (3 full lab reports @ 6% each; 2 short questionnaires @ 3%
each)
44% Final Exam (2 hours)
Course Syllabus available on LearnLink
What is Physiology?The goal of physiology is to explain the physical and chemical factors for the origin and progression of lifeORHow animals work!
Medical Physiology or Pathophysiology – abnormal physiology as the result of disease
Disciplines: Cellular Physiology, Developmental PhysiologyNeural, Renal, Muscle, Cardiovascular…… Physiology
Comparative, Animal or Integrative Physiology – how animal adapt to “abnormal” environments or life histories. Also environmental physiology, evolutionary physiology and physiological ecology
68 - 81ºC
2000-3000mHigh H2S
4000-5000m10% O2
0% O2!
When O2 removed happy produce ethanol
Hierarchical organization of the bodyCells
Tissues
Organs
Functional units
Organ Systems
Organism
Differentiated and specialized1) muscle, 2) nerve, 3) epithelial4) connective cells
Aggregate of specialized cells1) muscle, 2) nerve, 3) epithelial4) connective tissues
Subunits of an organs(e.g. multiple nephrons in a kidney)
Composed of the 4 tissue-types indifferent proportions and patterns
A collection of organs that functiontogethere.g. Circulatory System = heart,blood vessels, blood
Figure 1.2
Hierarchical organization of the body
Cells: in humans over 200 distinct kinds1) Muscle cells: specialized for contraction to produce movement
2) Nerve cells: generate and propagate electrical signals
3) Connective tissue cells: connect and support body structurese.g. bone, collagen, cartilage
4) Epithelial cells: secretion and absorption; protective rolee.g. skin
Subtypes can exist:– skeletal, movement of limbs and skin- cardiac, movement of heart- smooth, dilation of blood vessels, control of BP
Collection of organs that work together to accomplish a particular task
Simplified View of Overall Plan of Human Body
Fig 1.4
•Separates external from internal
•Keep constant internal envts.
•O2 in, CO2 out
The Internal Environment
Total Body Water = Intracellular H2O 28 L 2/3
Interstitial H2O 11 L
Plasma H2O 3 LECF 1/3
42 L or 60% body wt
Extracellular Fluid is rapidly transported by the circulation and mixes between blood and tissues by diffusion through capillary walls
Baths tissues and makes up the internal milieu of the body
See Fig. 1-5
Proper cellular function depends on tight control of ECF components
Fig. 1-5
HomeostasisA Defining Feature of Physiology
Claude Bernard (1813-1878)
Walter Cannon (1871-1945)
Extended Bernard’s notion to the organizationof cells, tissues and organs. First to coin the term “homeostasis”
Noted that mammals are able to regulate their internal environment withina narrow range.
“The maintenance of static or constantconstant conditions in the internal environment”
Regulatedvariable
Integrating center
input output
Set point
Effectors
Sensors
Negative feedback
Compensatory response
Basic Negative Feedback Control
Examples: arterial blood pressure, body temperature, pH, PCO2
See Fig 1.7
•Changes in the regulated variable is picked up by the sensors
•Reflex arcs = -ve feedback loop
•Set point compares input
•If s.p = input nothing happens within body
•If s.p ≠ input output causes a compensatory response using effectors, thus creating a –ve feedback
Lecture 2- Jan 5
• Reflexes: a key component of control systems
• Strictly defined as:» Involuntary, unpremeditated, unlearned response to a
stimulus
• Some are:» Learned or required
• Most are:» Attended by learning
Homeostatic control systems- reflex arc
Regulatedvariable
Integrating center
receptors output
Set point
Effectors
Negative feedback
Compensatory response
Stimulus or error signal +/-
Afferent Pathway
Efferent Pathway
Afferent Pathway: going to
Efferent Pathway: going away
•Restoration of set point never complete or exact and a persistent error signal keeps feedback loop in operation
•Hence the term “relatively” stable in definition of homeostasis
Afferent Pathway
Set Point Efferent Pathway
T-sensitive nerve endings
Compensatory Response
Fig 1.9
Intercellular communication
• Cell to cell communication is important for homeostasis• Performed by intercellular chemical messengers• 1) Hormones: Hormones secreting cells- target cells
through blood– Slow acting– Example: insulting and glucose homeostatsis
• 2) Neurotransmitter: Nerve- nerve; nerve- effector cell– Fast acting– Example: Acetylcholine and heart rate
• 3) Autocrine/Paracrine aagents: Local homeostatis responses– Act locally on target cell by difffusion– Examples includes ATP, nitric oxide (NO), fatty acid derivaties
(eicosanoids)– Auto= same cell; para= neighbough cells– See Fig 5.2
Cells and compartments
• Review 1st year material on cell organelles:– Nucleus, ER, Golgi, endosomes, lysosomes,
peroxisomes, mitochondria
• Membranes:– 1) important as selective barrier to movements in and
out of cells and organelles– 2) detect chemical messengers at the cell surface
Membranes•Integral proteins:
•Participate with chemical messengers•On the surface of the phospholipids bilayer
•Transmembrane integral proteins:•Inside the membrane•Has a pore that selectively allows movement in and out of the cell
•Peripheral proteins:•Attached to either inside or outside of the membrane
Integral proteins
Transmembrane integral proteinPeripheral
protein
-Extracellular membranes of adjacent cells joined
-Transport pathway between cells (extracellular) blocked
-Most substances must therefore go transecullarly
-Forms selective barriers
-E.g. most epithelial cells
Tight Junctions
•In tight junctions substances cannot pass from one cell to the other due to the close/tight proximity of the cells and thus the substances must pass thru transecullarly rather than thru extracellular pathways.
Desmosomes
-Hold adjacent cells tightly together
-Found in areas of stretching (e.g. skin) or highly mechanical stress (cardiac cells)
Gap Junction
- Protein channels (connexons) linking cytosols of adjacent cells
- channels are very small (1.5nm diameter) and limits what can pass
- connected in cardiac cells at intercalated disks and important for passage of electrical signals (Fig 14.8)
Mitochondria- Powerhouse of the cell
• Main function is to provide cell with energy in the form of ATP
• The site of cellular respiration (oxidative phosphorlyation)
Intermembrane space: space btwn inner and out membrane
Folded structure w/in inner membrane
Fluid in cristae
Mitochondria
• Outer membrane: Freely permeable to small molecules and ions
• Inner membrane: - Impermeable to most small molecules and ions including
H+- Contains respiratory complexes (ETC)
- ATP synthase (F0F1)
• Matrix:- Contains the citric acid cycle enzymes (Kreb’s, TCA)- Fat oxidizing enzyme (B-oxidation)- Pyruvate dehyrogenase (PDH)
Mitochondrial density is related to aerobic capacity
mouse elephantO2 c
onsu
mp
tion /
Mb
Mit
och
ondri
al densi
ty /
g
mouse elephant
Hummingbirdflight muscle
Humanmuscle
…cont’d
• Amount of mitochondria in cells can vary between tissues and animals
• Oxygen consumption of mouse is > than that of elephant
• And this mouse tissues have a lot more mitochondria than elephant
• Mitochondria is important in metabolism and ATP using O2
Biology 2A03Lecture 3
Protein activity&
Cell metabolism I
Membranes
Fig 2.15
•Look at different types of proteins we already looked at….
Mitochondria
Fig 2.20
•Look at different structures
•Enzymes of Krebs cycle in matrix
•ETC on cristae of inner membrane
•“power house” of cell (generates ATP)
•ATP powers physiological processes
•Outer membrane: freely permeable to smell molecules and ions
•Inner membrane: impermeable to small molecules and ions including H+
•Contains respiratory
•O2 used in oxidative phosphorylation in mitochondria
• O2 comes from respiratory system, delivered by blood circulation
• Burness, Science (2002) diagram
• Respiratory system getting O2 to lungs
• ATP is used for demand site, aids in:– Muscle contraction
– Ion pumps (to transport)– Protein synthesis
Protein activity & cell metabolism• Proteins and proteins functions are central to physiology• Protein activity is controlled by:
1. Rates of synthesis and/or degradation
2. Changes in 3D conformation (shape) determined by a.a composition, important for ligand binding to active binding site
• The shape of proteins and therefore ligand binding modified by:
1. Allosteric modulation: - non-covalent binding of factors to other regulatory sites results in a change in
shape of the active site.
2. Covalent modulation: - covalent binding of –ve PO42- to a.a side
chains by protein kinases
- changes in protein conformation and distribution of –ve charges
- eg., serine, threonine, tyrosine
• Proteins kinases add PO42- from ATP to proteins
• PO42- can be removed by protein phosphates
• Kinases can be controlled allosterically demonstrating that the 2 systems can interact
• Both allosteric and covalent modulation affect the binding affinity of enzyme for substrate (ligand) or a binding site can be turned off or on.
Fig 3-9, 3-10
1. Allosteric modulation
• Blue protein with green modulators
• The modulator binds to ligand and changes the binding site
of the protein
• Eg. Substrate for fat synthesis inhibits enzyme in
fat oxidation
2. Covalent modulation
• Phosphorylation and dephosphorlyation rxn
• Red triangle (phosphate groups) gets added to ligand
by enzyme
• Enzyme A: protein kinase adding PO4
2-
• Enzyme B: phosphatase removing PO4
2-
Enzymes
• Cell metabolism: sum of all chemical reactions that occur in cells
1. Anabolism (synthesis)2. Catabolism (breakdown)
• Virtually every chemical reaction in the body catalyzed by enzymes
• Often read cofactors (trace metals such as Mg, Fe, Cu, Zn)
• Or• Coenzymes derived from vitamins (eg., NAD+, FAD,
and coenzyme A from B vitamins)
Fig 3.4a
WHY DO WE NEED ENZYMES?
•Uncatalyzed they occur at too slow rate (yrs in some cases) due to high activation energy
•Enzymes decrease activation energy and increase reaction rates by a factor of 105 to 1017
• Enzyme kinetics: studying rate of reactions
• S= substrate
• E = enzyme (unused)
• Rates of enzymes reactions depend upon:1. Substrate [S] or product [P] concentration (Law
of Mass Action) - ↑ in [S], rxn goes right; ↓ in [P] rxn goes left
2. Enzyme concentration [E]
3. Enzyme activity (catalytic rate)
- Determines how quickly ligand binds to active site and is removed
S + E ES P +E Most important step
…cont’d
•As [S] ↑, VO
• Enzyme with higher affinity is able to catalyze the reaction at
a faster rate and will exhibit a higher degree of saturation
V0
[S]
½ Vmax
Km
Vmax 2x E
Change in affinity for Se.g. allosteric modulation
V0
[S]
1x E
Km
Relationship btwn [S] & rxn rate• The quantitative description of enzyme rxn reacts to [S],
constant Vmax and km occurs by the:• Michaelis-Menten equation:
VO = [S] Vmax
Km +[S]- Km = [S] at which VO = ½ max- If affinity ↑, then # of ES complex ↑ at any given [S] or
the same # of [ES] at lower [S] (ie, Km decreased)- In other words, at high affinities ½ Vmax occurs at a
lower [S]- Km can be determined from this plot- 1/ Km = affinity See Fig 3-7
Fig 3.8
Fig 3-7
•Enzyme 100% saturated with S at Vmax
•A fixed concentration of enzyme is assumed for this plot of reaction rate versus substrate concentration [S]. Binding of substrate to the enzyme
increases with increasing [S] until high substrate concentrations are reached, in which case all enzyme molecules are bound (100% saturation)
Increasing ES complex
Influence of substrate concentration on the rate of an enzyme-catalyzed reaction
•At lower and moderate concentrations, the rate of the rxn
increase as [S] increases
•At high concentrations, the curve level offs; when [S] is very high, the active site of every enzyme
molecule is occupied by substrate 100% of the time, and enzyme is
100% saturated.
BiologyLecture 4
Protein activity (cont..)
Transport I
Michaelis-Menten equation:
Relationship between [S] and reaction rateThe quantitative description of enzyme reaction rates to [S],
constants Vmax and Km occurs by the:
V0
[S]
½ Vmax
Km1
Vmax
Km = [S] at which the reaction rate Vo is equal to 1/2VmaxIf affinity increases then the #ES complexes increases, at any
given [S], or at the same #ES, the Km occurs @ lower [S]
Vo = ([S]*Vmax)/(Km + [S])
Km = 1/affinity
Metabolic pathwaysA sequence of enzyme-mediated reactions leading to a
specific product
P feeds back to E2 (allosteric inhibition)
A B C D PE1 E2 E3 E4
Specific reaction steps may be regulated to control fluxthrough an entire pathway.
Classically these are called rate limiting steps, but now we use“modern control theory”, which looks at the relative control
At each specific enzymatic step.
Metabolic Pathways – ATP Synthesis
One of the major roles of metabolic pathways is to convert potential energy into food (eg creates ATP for
use in cellular functions.
ATP
ADP + Pi
ATP consumption
Body uses ATP in movement, processing,
molecular transport/synthesis, etc
ATP production
Body converts fatsAnd carbs to ATP
ATP can be produced by:
NOTE – body tries to keep ATP levels relatively
Constant (homeostatic)
a) Substrate level phosphorilation
(done in the absence of O2)
c) Oxidative phosphorilation (uses O2 in the mitochondrion)
b) Kreb’s cycle (TCA citric acid cycle)
[ATP]
Transport mechanismsTransport across membranes
Membrane provide a selective barrier between the ICF and ECF(inter/extra cellular fluid)
*See Table 4.1 for differences between ICF and ECF
Transport mechanisms include:
1. Diffusion: simple movement across the lipid bilayer, does not directly consume energy (ATP)
See Table 4-2
2. Mediated transport: facilitated diffusion, or usestrans-membrane protein channels to move molecules
Active transport
Primary (directly uses ATP to move molecules)
Secondary (doesn’t use ATP, uses an electropotential difference between areas)
Simple diffusionDiffusion: “the movement of molecules from one location
to another due to random thermal motion
Movement is from a region of higher concentration to an area of lower concentration, until equilibrium is reached.
See Fig 4-2 Fig 4-4
Flux: movement from a compartment to another, per unit of time
Net flux = (F1-F2) flows towards the lower concentrationA gradient for diffusion is created, therefore downhill movement
Of the solute occurs.
F1 F2
The net flow is towards F2, butThere is flux both ways, unless
It is prevented by the cell membrane
F1 F2There is no net flow, as equilibriumHas been reached, however, there
Is still flux between the two areas
Net flux depends upon:1) Temperature ( ^^ Temp => ^^Flux)
2) Permeability (how porous is the membrane?)
3) Mass of molecule (larger masses are harder)
4) Surface area of regions ( ^^ SA => ^^ Flux)
Diffusion:- times (t) are proportional to the distance travelled (i.e. x^2)
- therefore is only efficient over short distances
For example transport of oxygen to cells, CO2 from cells)
Single cells can use diffusion rather efficiently
Large animals generally require the use of a circulatory system
BUT- both these systems work in conjunction, eg O2 is circulatedCapillaries, and then diffuses into the cells from the capillaries.
1a) Flux across the lipid bilayer
F = Kp × A× (Co - Ci)
is a measure of the ease of passage across a mebrane Kp:
It is a function of: i) Temperature factors
ii) Solubility in the bilayer (eg. Polarityunpolar/uncharged molecules have a high Kpwhile polar/charged molecules have a low KP
iii) Size and shape of the molecule (moleculeswith less complicated shapes diffuse easier)
See Fig 4-1Fig 4-10
Box p113
Diffusion continued
Flux
Permeability constant
Area
Initial concentration difference between
inside/outside of area of diffusion
Metabolic pathways• A sequence of enzyme-mediated reactions leading to a
specific product:
A ↔ B ↔ C ↔ D ↔ P E1 E2 E3 E4
- Allosteric inhibition (end product inhibition)
• Specific reaction steps may be regulated to control flux through entire pathway
• Classically these are called “rate binding” steps but modern critical theory does not use this term
– Critical theory: looks at the relative control each enzymatic step
Biology 2A03Lecture 5
Transport Mechanisms II
2a) Diffusion through transmembrane protein channels
Important for the movement of charged ions which normally do not diffuse across lipid bilayers
Na+, K+, Cl- and Ca2+ pass through the membrane with the aid ofselective transmembrane proteins channels
Both diffusion and electrical forces important for movement of ionsalso called electrochemical gradient.
Membrane potential involves the seperation of charges across aMembrane, creating an electrochemical gradient while allows for
Diffusion is required.
Fig 4.2
– Separation of charge = potential energy
Separation of Charge Across a Membrane
–Electrical forces• act similar to diffusion,
movement towards lowest concentration
–Membrane potential is negative (always relative to
inside)• + goes INTO the cell
• - goes OUT of the cell (due to the electrochem
gradient–Magnitude of electrical
driving force • depends on the valence
of the ion being driven
ITC = neg charges ETC = pos charges
Electrochemical Driving Forces
Direction of ion movement depends on balance between electrical and
Chemical forces
If these are equal the electrochemical force is ZERO
For this example: (TOP) Chem > Elec Forces, therefore
there is a net movement outwards
(BOTTOM) Elec > Chem forces, sothere is a net movement inwards
Fig 4-5
Ek= equilibrium potential whichreflects the driving force of the
movement.
Fig 4-13
Selective for type of ion -due to size and the charged
and polar surfaces of the protein subunits of the
channels
Channel Protein
Electrically repel/attract certain ions, through a Channel Protein,
which consist of polypeptides around a central core, which
creates the channel to transport the ions.
Opening of the pore can be regulated, often through conformational changes of the protein, eg phosphorilation, etc.
2b) Facilitated Diffusion (actually a mediated transport)
Net flux of molecules across membranes is from a high Concentration to a low concentration (downhill movement).
Not coupled with ATP hydrolysis to move molecules uphill.
Flux 1 >> Flux 2
ECF = ~6mM ICF = ~1 mM
Glucose glucose
Glucose-6-phosphate
Fig 4-11Fig 4-12
Mediated transport can also become saturated and reach
maximal flux. Simple diffusion will increase, and cannot
become saturated.
Differs from simple diffusion in that it involves selective
membrane transporters for large or polar molecules.
The substrate bonds, causing a conformational
change in the protein.
Bind substrates and undergoes conformational changes
2c) Primary active transport
Direct use of ATP to power movement of molecules against anelectrochemical gradient or uphill
Covalent modulation of transporter (by phosphorilation through ATP) Increases the affinity of the binding site, and so the efficiency of the
Protein.
Dephosphorylation occurs by conformational change of the transporterAnd decreases the affinity of the binding site.
Examples include: Na+ / K+ -ATPase, Ca2+ -ATPase, H+ -ATPase
H+/K+ -ATPase
Intracellular K+ = 15 mM, extracellular K+ = 4 mMInward movement of K+ is uphill (against the gradient)
And so requires the use of ATP to facilitate diffusion.
See Table 4.1
Intracellular K+ = extracellular K+ =
Inward movement of K+
Intracellular Na+ = 15 mM extracellular Na+
=145 mM
Outward movement of Na+
Fig 4-14
2c) Primary active transport
Note that an uneven distributionOf charge is created here.
Membranes are “leaky” to ions
Ion pumping to maintain proper Gradients, produces heat as a
by-product (up to 50% of cellularHeat production is done this way).
Endotherms have leakier membranes than ectotherms (i.e. allow for
ionic exchange much easier) This results in a metabolic rate that is often 10 times that of the samesize ectotherms.
2b) Secondary active transport
Uses [ion] gradient across membrane as a source of energy
As ion moves down its concentration gradient it provides energy foruphill transport of another atom.
Usually Na+ whose binding changes the affinity of the transporterProteins for solute, via ALLOSTERIC MODULATION.
Primary active transport is needed to maintain the electrochemicalGradient which allows for secondary active transport.
This example is of cotransport/symport
- net binding increases the affinity ofthe protein for a second molecule.
Can also occur in opposite directions =
Countertransport/antitransport
High glucose
High H+
Biology 2A03Lecture 6
Signal transduction
Osmosis
Water diffusion: although water is polar it has high permeability in membranes due to its small size
Flux can be increased by the presence of aquaporins = protein channels
H2O concentration depends on the # of dissolved particles
Total [solute] in solution determines osmolarity (colligative properties)
1 mole of dissolved particles = 1 osmolar solution
e.g. 1M of glucose in solution = 1 osmolebut 1M of NaCl = 2 osmoles since it ionizes in solution to Na+ and Cl-
The higher the osmolarity of a solution the lower the H2O concentration
Osmosis in the direction of higher osmolarity (or lower [H2O])
Hypertonic:
Hypotonic:
Isotonic:
Fig 4-19
Cells are very permeable to water and impermeable to many solutes
Extracellular fluid has the same # of osmoles of nonpenetrating solute
Extracellular fluid has a greater # of osmoles of nonpenetrating solute
Extracellular fluid has the lower # of osmoles of nonpenetrating solute
Cell shrinks
Cell swells
No change in cell volume
300 mOsm
400 mOsm
200 mOsm
Compare to osmolarity
Relates the osmolarity of a solution relative to normal extracellular fluid without regard to penetrating or nonpenetrating nature of
solutes
A solution can be isoosmotic at 300 mOsm but hypotonic due topenetrating solutes
isoosmotic But hypotonic
300 mOsm >300 mOsmnonpenetrate
penetrating
4 features of signal transduction pathways:
Signal Transduction Pathways detect intercellular messengers and convert them into a biologically meaningful response
2) Amplification:
3) Desensitization / adaptation:
4) Integration:
The signal molecule fits in its receptorwhile others do not
Feedback shuts offreceptor or removes it
1 receptor binding can lead to 1,000,000 products
response- +
Outcome the result of integrationof both receptor inputs
1) Specificity:
Can also have messenger bind to multiple receptors with different affinities
ReceptorsThe magnitude of a cell’s response depends on:
1) the messenger’s concentration
2) the # of receptors present
3) affinity of receptor for messenger
Show characteristics very similar to enzymes
Fig 5-9Fig 5-10
Can become saturated with messenger
An increase in the # of receptorsincreases the % bound with messenger
Change in affinity for messenger
Can increase # of bound receptorsat the same [messenger]
Fig 5-10
Or…50% of the receptors are bound at a lower [messenger]
Receptors can be intracellular:
RM
R
See Fig 5-11
bind to lipophilic messengers
alters synthesis of a specific protein-act as transcription factors
Receptors can be located in the cytosol of in the nucleus
e.g. steriods = hormones
Receptors can be membrane bound:1) Channel-linked:
3 main types(e.g. binding opens ion channel)
Fig 5-12
Bind lipophobic messengers
Called ligand-gated channels
This is an example of a “fast” channel
Channel also acts as the receptor
Allows channel to open quickly and briefly
2) Enzyme-linked:
Binding activates tyrosine kinase activity which phosphorylates a protein - on
tyrosine
Ligand-binding domain on extracellular surface andan enzyme active site on intracellular side
Fig 5-13
e.g. insulin receptor
3) G-protein-linked: (activate membrane proteins called G-proteins and begin a signaling cascade)G-proteins can be stimulatory (Gs) or
inhibitory (Gi)
2. Often activates an enzyme
Fig 5-14
1. Regulates a protein channel
e.g. Can open or close a“slow ” ion channel
- Channel does not act as receptor
e.g. adenylate cyclase to produce cAMP
α-subunit binds GTPto become active
Important 2nd messengers are:1) Ca2+
2) cAMP3) cGMP4) DAG
5) Eicosanoids6) IP3
Second messengers
Intercellular chemical messenger which reaches the cell surface is called the first messenger
The intracellular messenger produced by the binding of the first messenger is called the second messenger
Act as chemical relays from the plasma membrane to the biochemical machinery inside the cell
Table 5-3Fig 5-16Fig 5-17Fig 5-18
Extracellular fluidMessenger
1 Receptor
GDP GTP
GDP GTP
2
Amplifierenzyme
Secondmessenger
Protein kinase
Activatesenzyme
Protein
ATP
+Protein – P
ADP+
3
4
5
6
Response in cellCytosol
Substrate
Adenylate cyclase
ATPcAMP
blood borne hormoneepinephrine
1x molecules
β-adrenergic receptor
G-proteinstimulatory 20x molecules
10x moleculesPKA
inactivePKA
active
-Example of a signal transduction pathway-Next slide
glycogen Glucose 1-P
inactivePhosphorylase b
Kinase
activePhosphorylase b
Kinase
inactiveGlycogen
phosphoryase b
activeGlycogen
phosphoryase a
(100x molecules)
(1000x molecules)
(10,000x molecules)
Amplificationof hormone signal
Adrenergic receptor can be desensitized by phosphorylation
Response of the cell (e.g. glycogen breakdown in liver cells)PKA
active10x molecules
PKAactive
Glycogen synthase (inactive)
Biology 2A03Lecture 7
Circulation I
Circulation
Why have a circulatory system?
Diffusion times (t) are proportional to the distance covered
Diffusion gradients for nutrients or wastes can decrease drasticallyover large distances.
Diffusion is sufficient in a unicellular organism.
Multicellular organism’s require a circulatory system, as the distances
for diffusion are too large to be efficient.
High [waste] inside forcesWaste to flow to the outside.
Waste outNutrients in Nutrients in
Waste out
Circulatory SystemsA fast convection system = rapidly circulating fluids
between surfaces that equilibrate external milieu (environment) for cells deep inside an organism
1˚ role =
2ary role =
System consists of:
1) Fast chemical signalling
2) Dissipating heat
3) inflamatory/heat defences against micro-organisms
distribution of dissolved gasses and molecules from nutrition, growth, and repair.
1) A Convective medium = blood (communication system)
2) Plumbing = blood vessels (regulates blood pressure/distribution)
3) A Pump = heart (sensory and endocrine (hormonal) functions)
Fig 14-2
The Circulatory System1. Pulmonary circulation (lungs)
Low pressure system (20mmHg)
2. Systemic circulation
Delivers O2 to tissue and organs,NOT the lungs.
High pressure system (100mmHg)
Composed of 2 circuits
Both have an arterial components (blood FROM the heart) and a
venous component (blood TO the heart).
*flow through each of these circuits is
EQUAL!!!!
Picks up O2 from the lungs
Right ventricle lungs
Left atrium
Left ventricle Organs and tissues
Right atrium
Blood – plasma & cells (erythrocytes, leukocytes, platelets)
Composed of:
1) Plasma ~92%water
proteins ~7%
Electrolytes (ions)
gases
nutrients
wastes
Albumin, antibodies,
Major Cation (Na+ 145 mM)Major Anion (Cl- 100,140
mM) O2, CO2, N2
Glucose, lipids, amino acids
Urea, ammonia
See Table 16-1
-ISF and plasmavalues close to each
other-Except that
proteins > in the plasma
The capillary wall is very permeable to H2O and most plasma components,Except for proteins, based on their shape, size, and charge.
Hematocrit
ll
The fraction of blood composed of Red Blood Cells (RBC’s/erythrocytes)
Hematocrit =
lt
lt
l1
Can be measured after blood is centrifuged in a microhematocrit tube
Lightest
Most dense Total blood vol = ~5.5 L Plasma (54%) = ~3.0 L RBC’s (45%) = ~2.5 L
Plasma ~54%
Eryhtrocytes ~45%
Buffy coat (leukocytes and platelets) ~1%
2) Blood Cells – 1. Red blood cells (erythrocytes)
Most abundant cell in the blood stream-Major function to transport O2 from the lungs
CO2 from the tissues
-Contain large amounts of hemoglobin (85% of
protein content) for carrying O2
-In mammals do not contain nucleus/organellesand so cannot divide (transporter for the body)
-and the enzyme carbonic anhydrase important for CO2 transport
-Shape of cells important for O2/CO2 diffusion -Biconcave disk – thicker at the edges, gives a high SA/Vol ratio,
which provides easier diffusion, and greater flexibility, whichalso allows for easier diffusion.
280 x 106 Hb molecules per RBC
Hb exhibits the property of allosteric modulation = “binding at one site on a molecule affects binding at a
second site, usually by changing the shape of the molecule.”
Hb is a tetramer (M.W. ~ 68,000), composed of 4 sub-units
Each unit consists of a “heme” ring structure, & a polypeptide chain (globin) which binds CO2, H+,
phosphates, etc, which change the affinity of hemoglobin for O2
Regulation of erythrocyte production
Blood components are under tight reflex (homeostatic) control
Red blood cell production occurs in bone marrow
Have relatively short (120 days) life span (compared to other vertebrates)
Approximately 1% per day breakdown occurs in spleen and liver
Product= bilirubin (yellow colour)
Production (erythropoiesis) is primarily regulated by the hormoneErythropoietin (EPO), which is secreted by specialized cells in
the kidney.
Increased release triggered by a decrease in O2 delivery to the
kidney. Fig 16-4
Regulation of erythrocyte production
Fig 16-4
O2 delivered to the kidney
EPO secreted by the kidney
Plasma EPO
Production of RBC’s in Bone marrow
Blood hemoglobin (HB)
Blood O2 carry capacity
Restoration of typical O2Delivery, cycle is re-balanced
Ways to increase red blood cells
High altitude: low levels of O2 stimulates production of RBC’s
Blood doping: previously stored RBC’s are injected into people.
Epo: requires ~3 wks to clear system, allows for window ofTesting times for athletes…resulted in stripping of medals.
Polycythemia: RBC’s (hematocrit) levels are too high. An increase in viscousity makes circulation difficult.
Anemia: Low ability for 1) Carrying RBC’s 2) Low HB per RBC ,or 3) both
Definitions
2. Leukocytes- eosinophils, basophils, neutrophils, moncytes, lyphocytes
-Produced in bone marrow and lymphoid tissue
-Defense and cleanup functions
3. Blood platelets – important for hemostasis
-Formed by the breakdown of WBC’s
-Involved in blood clotting
-Form a platelet plug to stop the bleeding
“Buffy coat”
Both of these types are cells are much less numerous in the blood than RBC’s
Biology 2A03Lecture 8
Circulation I
Q (or F) = ΔP
R
P1 P2
R
Q
The fundamental law of the circulation.
.
ΔP = pressure difference between 2 points in a circulation system.
R = friction that impedes flow (not measured directly, but is calculated)
P = force/area exerted by blood – generated by heart contractions.
Internal friction (viscousity) External friction (friction with vessel wall)
R increases
Q decreases (flow slows)
Q (or F) = ΔP
R
The fundamental law of the circulation - Pressure.
ΔP = MAP – CVP
= 90 – 0 mmHg
= 1 Systolic P + 2 Diastolic P
3
MAP a weighted average of the time spent in each phase.
MAP is the overall pressure driving the blood into the tissues.
Fig 15-2
…where,
MAP = mean arterial pressureCVP = central venous pressure
Systemic vs Pulmonary PressuresΔP = MAP- CVP
Systemic = 90 mmHg Pulmonary = 15 mmHg
Recall: that Q = 5 L/minfor each circuit.
And: Q = deltaP/R
Therefore: R must be lower in pulmonary curcuit.
Fig 15-3 Also NOTE: Q pulmonary is equal to the Q systemic, allowing foran even flow of blood through the system.
Low pressure low resistance circuit
1) Prevent fluid filtration in the lungs
3) Minimizes workload of the right ventricle.
High pressure & resistance circuit
1) Ensure good fluid filtration in the systemic capillaries
to ensure nutrient distribution.2) Rapid shunting of blood
3) Left ventricle has a high workload as a result of 1) and
2).
2) Prevents shunting of blood
Pulmonary Systemic
Fig 14-5
Right ventricle left ventricle
Shunting = the movement of blood in the body between
compartments, through thecirculatory system.
Poiseuille’s Law
π r4
8 η LR= -L of blood vessels is fairly constant. -Viscosity (η) is also fairly constant.
-Radius the most important factor in determining the resistance.
R α 1r4
e.g. Decreasing r by 2x Decreases flow by 16x
Q= π r4
8ηl
ΔP
What determines vascular resistance?
L
rQ
Polycythemia and decreased T˚C
Anemia and increased T˚C
constant
Since R=ΔP
Q
Polycynthemia = increase in # of RBC’s
Due to the constants, the resistance is dependant on
the radius.
Biology 2A03Lecture 9
Circulation III
Resistance vesselsCapable of active and passive changes in radius
Active (smooth muscle contractions)Passive (stretch in the capillary)
arterioles & pre-capillary sphincters have smooth muscle
for active changes in radius.Addition of R’s
In series
R1 R2 R3
RT = R1 + R2 + R3
Resistance greater thanany single R
R1 R2 R3
1/RT = 1/R1 + 1/R2 + 1/R3
In parallelResistance is smaller
than any single R
RT= 1/ (1/R1 + 1/R2 + 1/R3)
Most major resistances are arranged in parallel.
Portal circulation an example of resistance in series (i.e. all capillaries
are working together to do thesame thing.
Fig 14-3
Capillary networks are small vessels arranged in parallel
Even though r is small per capillarytotal resistance of all capillaries
is relatively significant, due to the large number of capillaries in the
system.
Total Peripheral Resistance (TPR)
Combined resistance of all blood vessels within the systemic circuit
Resistance across a network of blood vessels depends on the resistance of all vessels.
Flow through network varies with resistance.
Vasoconstriction in network increase resistance decreases the flow
Vasodilation in network decrease resistance increases the flow.
Relating Pressure Gradients and Resistance in the Systemic Circulation
– Flow = cardiac output (CO)
– ΔP = Mean Arterial Pressure (MAP)– R = Total Peripheral resistance (TPR)
Flow = ΔP /R
CO = MAP/TPR
Arteries ~12 mm
Arterioles~ 15
micrometresCapillaries~3
micrometresVenuoles ~10
micrometresVeins~5 mm
Low resistance, little pressure drop, acts as a pressure reservoir.
Major site of resistance, controls bloodflow patternshelps regulate arterial blood pressure.
Exchange site of nutrients and metabolic biproducts
Exchange of nutrients, O2, CO2 (but only a very small amount)
Low resistance, thin walled, distensible (stretchy),adjusts blood return to heart, and acts as a blood
reservoir (can/does hold ~60% of the blood volume)
All parts of the circulatory system have endothelium (inner layer), all but capillaries have smooth muschle and connective tissue (outer layer)
mic
roci
rcu
lati
on
Inner radiusVascular system
See Fig 15-6
Varying degrees of elasticity and collagen fibre content.
Connective tissue
Smooth muscle
Endothelium(single layer of cells, which
allows for easy diffusion.
Fig 15-5
Capillaries contain a singlelayer of cells for easy diffusion
of blood.
Veins/arteries have valvesTo ensure a one-way flow
Of blood in the system.
ArteriesMuscular, highly elastic - High elastin to collagen ratio in
connective tissue
Compliance = ΔPΔV moderate compliance to smooth out
pressure fluctuations from the heart.
Large changes in pressure with small changes in volume make
arteriespressure reservoirs.
Large changes in volume with With small changes in pressure make veins volume reservoirs.
Fig 15-20
The higher the compliance the greater a vessel can be stretched,and therefore the higher the amount of elastin in the tissue.
Stores pressure which is then released between ventricle
contrations (diastole => relaxed)
Pressure stays in the walls when relaxed.
Arterial walls recoil during diastole, pushes blood
forwards and maintains blood flow at a constant
level.
Arteries as pressure reservoirs
Fig 15-7
Only 1/3 of the stroke volume(the volume the heart ejects per
contraction. Blood leaves the arteries at this time.
Pressure peaks during ventricular ejection (systole) = Systolic Pressure (SP), lowest is Diastolic Pressure (DP)
between contractions.
SP-DP = Pulse Pressure (PP)
Depends on speed of ejection, stroke volume and complianceof arteries – (low compliance = high PP)
e.g. hardening of arteries decreases ampherence(?) and PP
systolic
diastolic
PP
Arterioles are the major site of resistance in the circulatory system.
Biology 2A03Lecture 10
Circulation IV
Arteries as a pressure reservoir
Fig 15-7
•Stores pressure which is then released between ventricle
contractions (diastole), great increase in P with a small
increase in V
•Only 1/3 of the stroke volume leaves the arteries at this time
•Arterial walls recoil during diastole (heart relaxed) and
this maintains bloodflow constant
systolic
diastolic
•Shows pressure fluctuation during systole and diastole
•Pressure peaks during ventricular ejection (systole) = systolic pressure (SP), lowest is diastole pressure (DP) between contractions
•SP-DP = pulse pressure (PP)
•PP depends on stroke volume, speed of ejection and compliance of arteries – (low compliance high PP) e.g. hardening of arteries, decreases
compliance and increases PP
•Huge drop in pressure, because this is the major site of restriction in the circulatory system
PP
Arterioles2 roles:
Control of vascular smooth muscle
Local (intrinsic)•Paracrine•E.g active hyperemic
Extrinsic1. SNS through NT norephinephrine (NorEpi)
2. PSNS (ParaSNS) not very important in controlling arterial radius
3. hormones
1. Determines relative bloodflow to tissues• E.g rest to exercise muscle bloodflow 1L/min to 20L/min
2. Helps regulate Mean Arterial Pressure (MAP)
• Major site of resistance in cardiovascular system, Largest ∆P
• Adjust resistance of vessels going to tissues by adjusting radii both passively (stretch) and actively (nerves, hormones, etc)
• Are well innervated (nerve terminal exists here) and contain smooth muscle that contracts (vasoconstriction) or relaxes (vasodilation)
• Always some intrinsic tone (basal tone) plus tonic constriction due to basal firing of Sympathetic Nervous System, e.g when standing
Active hyperemia•Local chemical change causes bloodflow to increase in proportion to
metabolic activity of that organ•Way organs are able to match their metabolic activity with the delivery of
nutrients and exiting of wastes•↓ oxygen, ↑ carbon dioxide, ↓pH, ↑ adenosine, etc.
•Products of metabolism act on blood vessels and cause vasodilation and increases bloodflow act on –ve feedback
•Occurs in heart and skeletal muscle since it has large variation in metabolic rate
•Other intrinsic factors : Endothelim-1 (vasoconstriction), NO (nitric oxide, vasodilation)
See Fig 15-13
Fig 15-12
•Affects contraction of smooth muscle in vessel
wall
Reactive hyperemic•Triggers are same but trigger reasons are different
•Decrease in bloodflow causes metabolites to changes and trigger an increase in bloodflow
Myogenic response•Change in vascular resistance in response to stretch of
blood vessels in absence of any external factors•Regulate bloodflow to be constant in tissues in phase of
stretching the vessel
Fig 15-14
Increase in blood entering the tissue
Extrinsic controls
SNS
PSNS: Not a big role in vascular smooth muscle regulation
Hormones: Epinephrine from adrenal medulla causes vasoconstriction via α-adrenergic receptors, vasodilation via B2-
adrenergic•Skeletal muscle have alpha and B2- adrenergic receptors
•In most vascular beds, alpha outnumber B2 (except in skeletal muscle)
•Epinephrine has greater affinity for B2 receptors
Table 15-2
•Arterioles highly innervated and have α-adrenergic receptors (post-synaptic) which trigger vasoconstriction through NorEpis
•Changes above or below tonic constriction (nerves always active)
•Important role in controlling whole body arterial blood pressure
Fig 15-15
•Distribution of bloodflow at rest•During exercise, huge increase in bloodflow to skeletal muscles
•High [Epi] – binds alpha and B2 receptors•Vasodilation in skeletal and cardiac muscle vascular beds
•Decrease TPR•Vasoconstriction in most vascular beds
•A way of maintaining TPR maintain blood pressure•Dominant effect usually vasoconstriction
Other vasoconstrictor hormones
•Angiotensis II – renin – ANG system•Vasopressin – posterior pituitary
•Endothelin-1 (mostly acts as peptide paracrine against release by endothelial cells)
Vasodilator hormones
•Atrial natriuretic hormone – secreted by the heart
See Table 15-1
Metarterioles & Precapillary sphincters•Passive and active changes in radius and R
•Both contain rings of smooth muscle, no innervation, only affected by local factors (intrinsic control)
Fig 15-8
•Metarterioles act as bypass channels or shunts
from arteries to venuoles
•When resistance is low, blood may bypass capillary
bed
Capillaries
Important for:
•Thin walled tube of endothelial cells
•Permeate most tissues and cells (any cell in body) generally within 1mm from a capillary
•Small in radius but networks have large surface area ~ 10-40 billion capillaries for a combined surface area of 6000m2
1. Exchange of materials between blood and cells.
2. Normal distribution of ECF (composed of plasma & ISF)
• Increased SA leads to lower blood velocity, important to
maximize time for exchanging nutrients and wastes
1) Continuous capillaries
Endothelial cell cleft
2) Fenestrated capillary
plasma
Fenestrations(pores)
Intercellulargap
See Figure 15.16a+bFigure 15.17
proteins
O2, CO2
O2, CO2
Na+, K+
proteins
• Most common type
• Small spaces (water-filled cleft) btwn endothelial cells
• Very permeable to lipid soluble molecules
• Less for water soluble solutes and proteins (passage restricted to water-
filled cleft)
• Proteins too large to pass through clefts• Also called sinusoidal capillaries
• Fenestrations can be large enough to allow large proteins or entire cell pass
(ex. WBC)
• High permeable capillaries
• Abundance in:
• Liver- plasma proteins synthesized (e.g albumin)
• Bone marrow- blood cell production
Bulk Flow
4 main forces determining direction of flow:
1) Capillary hydrostatic pressure (PCAP) filtration
2) ISF hydrostatic pressure (PISF) absorption
Two hydrostatic pressures due to fluids:
Two osmotic pressures (due to presence of non-permeating proteins – called oncotic pressure)
4) ISF oncotic pressure (ΠCAP) filtration
3) Capillary oncotic pressure (ΠCAP) absorption
Favours:
• Very important homeostatic mechanism
• Capillary membranes freely permeable to water and small solutes
• Net flow of fluid from plasma to ISF= filtration
ISF to plasma= absorption
• Role is to maintain fluid balance btwn plasma and ISF = ECF
pre
ssure
Arterialend
Venousend
Bulk flow: net fluid flow across capillaries depends on the difference in filtration and absorption pressures
Net filtration pressure (NFP) =
PCAP= 38 mmHg PCAP= 16 mmHg
π ISF= 0 π ISF= 0PISF= 1 PISF= 1
π CAP= 25 mmHg π CAP= 25 mmHg
See Fig 15-18Table 15-3
(PCAP + (π CAP + π ISF) - PISF )
arterial venous
filtration
absorption
NFP = (38 + 0) – (25 + 1)
= + 12 mmHg
NFP = (16 + 0) – (25 + 1)
= - 10 mmHg
Because no proteins at ISF Blood Pressure
Osmotic Pressure
NFP -
NFP +
Biology 2A03Lecture 11
Circulation V
1) Continuous capillaries-More common type
-Small spaces (H20-filled cleft) between endothelial cells
-Very permeable to lipid soluble molecules
-Less for water soluble solutes & proteins (passage restricted to H20-filled cleft)Endothelial cell cleft
2) Fenestrated & sinusoidal capillaries
-Fenestrations can be large enough to allow large proteins or entire cells pass
(e.g. WBC)
-Highly permeable capillaries
-Liver – plasma proteins synthesized (e.g. albumin)
-Bone marrow – blood cell production
plasma
Fenestrations(pores)
Intracellulargap
O2, CO2
Na+, K+
proteins
proteins
-Proteins too large to pass through clefts
O2, CO2
See Figure 15.16a+bFigure 15.17
Bulk FlowCapillary membranes freely permeable to H2O and small solutes
Net flow of fluid from plasma to interstitial fluid (IF) = filtrationinterstitial fluid to plasma = absorption
The role of bulk flow is to maintain fluid balance between plasma and IF = ECF
4 main forces determining direction of flow (Starling-Landis forces)
1) Capillary hydrostatic pressure (PCAP) filtration
2) IF hydrostatic pressure (PIF) absorption
Two hydrostatic pressures due to fluids:
Two osmotic pressures (due to presence of non-permeating proteins – called oncotic pressure)
4) IF oncotic pressure (π IF)
absorption3) Capillary oncotic pressure (π CAP)
filtration
favours
Osmotic pressure
Blood pressure
pre
ssure
Arterialend
Venousend
Bulk flowNet fluid flow across capillaries depends on the differencein filtration pressure and absorption pressures
filtration absorption
Net filtration pressure (NFP) =(PCAP + π IF ) – (π CAP + PIF)
PCAP=38mmHg PCAP=16mmHg
π IF=0 π IF=0PIF=1 PIF=1
π CAP=25 π CAP=25
NFP +
NFP -
NFP=(38 + 0) – (25+1) NFP=(16 + 0) – (25+1)
+12 mmHg -10 mmHg
See Fig 15-18Table 15-3
arterial venous
Filtration usually exceeds absorption with 3-4L entering
IF (= total plasma volume !)
This fluid is returned to the circulatory system by the
lymphatic systemLymph flow = ~4L/day
If not returned to circulation get edema
Extreme case failure of lymphaticsystem to clear fluid = elephantiasis
Due to low pressures there is normally no filtration in lung
capillariesFig 15-19
Filtration ~ 20L / dayAbsorption ~ 17L / day
Venuoles and veins
Return blood back to the heart (via vena cava) and act as a volume reservoir (50-80% of blood volume – vasoconstr. or dil.)
Necessary force provided by ΔPbetween peripheral veins (10-15mmHg)and right atrium (~0mmHg).Adequate because of low R of veins
Veins also have one-way valves that ensure movement towards the heart
Venous return has a major effect of volume ejected by the heart= stroke volume
Thin-walled and highly compliant vessels to accommodate large volumes for small changes in pressure (“capacitance vessels”)
Venous pressure depends on volume of blood; nerve, hormonal and
paracrine regulation of smooth muscle; respiratory & skeletal muscle pump
One-wayvalves
Skeletal muscle pump – muscle contraction increasesVenous pressure
Lower value closes and upper valve opens – reverse when muscle relaxes
Fig 15-22
The Heart
Composed of 3 layersOuter epicardium (connective tissue)
Myocardium (muscle)
Endothelium (extends throughout the CVS)
**Know functional anatomy and bloodflow patterns (see p421-422)
Mean arterial pressure (MAP) = CO x TPR Q x RΔP =
hr x SV
Cardiac muscleComposed of 3 cell types
1) Contractile cells: majority of cells (99%)- have properties of skeletal(striated – actin and myosin) and smooth muscle (gap junctions)
All cardiac cells interconnected (as a syncytium) through Gap junctions – protein channels linking cytosols – small in diameter
Concentrated at intercalated disks which contain connections that hold the cells tightly together and resists mechanical stress (desmosomes)
Fig 14-8
2) Pacemaker CellsDetermine the rate the heart beats
Located in 2 regions:
Two cell types display autorhythmicity: Spontaneously generate action potentials (AP’s)
i) Sinoatrial node (SA) ii) Atrioventricular node (AV)
SA has a higher intrinsic rate (70 impulses/min) than the AV node(50 impulses/min).
Can take over if SA fails or transmission toAV is blocked
AP - Membrane potential changes soinside of cell become (+) relative
to outside
Fig 14-11
3) Conduction fibers (Bundle of His & Perkinje fibers)Rapidly conduct (4m/s) AP generated by the pacemaker cells
Cell-cell rate through gap junctions is 0.4m/s
The heart consists of 2 syncytiums (atriums and ventricles)connected by conduction fibers
Fig 14-9
(pacemaker)
Fastest depolarizing cells drive all other cells (they are linked together by gap junctions) =
pacemaker = sets pace for entire heart
Location Firing Rate at Rest SA Node 70-80 APs/min AV Node 40-60 APs/min Bundle of His 20-40 APs/min
Purkinje Fibers 20-40 APs/min
Autorhythmic Cells
Heart affected by changes in rates of AP generated by pacemaker
Regulation of heart rate (hr) (both rate & force are regulated)
Pacemakers get direct input by autonomic nervous system
SNS NE Acts on SA and AV nodes via β1 adrenergic receptors to increase hr
PSNS ACh Acts on SA and AV nodes via M2 muscarinic receptors to decrease hrVegus nerve
Cardiac nerve
(acetylcholine)Predominant factor in setting resting
heart rate of 70 bpm (rate without any inputs = 100bpm)
SNS and PSNS haveopposite effects
NOTE: SNS has more connections to myocardium
(more effects on forcethan PSNS)
Hormones (e.g. epinephrine) can affect heart rate
Increases hr via same mechanisms as SNS
Temperature: directly alters the intrinsic rate of the SA nodeChanges hr by 15bpm / ˚C
e.g. 1 deg fever hr is ~85 bpm
Regulation of heart rate (hr)
Sequence of electrical events that triggers a heartbeat
1 AP initialed in SA node
AV node
Internodal & interatrialpathway
Spreads throughatrial muscle
2 Transmission slows down atthe AV node by ~0.15sec
3 AP transmitted through theAV node to the Bundle of HisDivides into the left and right
bundle branches
4 AP enters a network of branchesalong the ventricle muscle:
Purkinje FibersImpulse travels through ventricle
from apex towards valves
Fig 14-10
Ventricles have coordinated contractions
Separates atrial & ventriclestimulation
Biology 2A03
Lecture 12Circulation V
The Heart
Composed of 3 layers• Outer epicardium (connective tissue)
• Myocardium (muscle)
• Endothelium (extends throughout the CVS)
Divided into 4 chambers separated by valves (ensure unidirectional flow)
•Walls thickness depends on work performance•Atria only pump to the ventricles
•Right ventricle only pumps to pulmonary circuit•Left ventricle thickest wall because it performs most work
pumping to rest of the body
**Know functional anatomy and bloodflow patterns (see p421-422)
Mean arterial pressure (MAP) = CO x TPR Q x RΔP =
hr x SV
Fig 14-1•All arteries don’t carry oxygenated blood
•Valves ensure that bloodflow is in only one direction
Functional anatomy and bloodflow patterns (see p421-422)
• Heart has four valves that keep blood flowing in the proper direction
• Atrioventricular valves (AV valves)– Separate atrium and the ventricle– Permits blood to flow from the atrium to the ventricle– When atrial pressure is higher than ventricular
pressure, the valves open– When ventricular pressure becomes higher than atrial
pressure, the valves close• Bicuspid valves (BV) or mitral valve
– AV valve on the left has two flaps or cusps of connective tissue and thus called BV
• Tricuspid valve (TV)– AV valve on the right has three cusps and called TV
Fig 14-6
• Semilunar valves– Located between the ventricles and arteries– Aortic semilunar valve is located between
the left ventricle and the aorta– Pulmonary semilunar valve is located
between the right ventricle and the pulmonary trunk
– Function similar to AV- make blood flow in one direction and prevent it from flowing in opposite direction
Fig 14-7
Cardiac muscleComposed of 3 cell types:-
1) Contractile cells: majority of cells (99%) have properties of skeletal (straited-actin and myosin) and smooth muscle (gap junctions)
• All cardiac cell are interconnected (as a syncytium) through Gap Junctions- protein channels linking cytosols-small in diameter (electric
current)• Concentrated at intercalated disk which contain connections that hold
the cells tightly together and resist mechanical stress (desmosomes)• Sarcomeres are units of myosin and actin
Fig 14-8
2) Pacemaker Cells• Determine the rate of heart beats
• Located in 2 regions:-
Two cell types display autorhythmicity: Spontaneously generate action potentials (AP’s)
i) Sinoatrial node (SA) ii) Atrioventricular node (AV)
• SA has a higher intrinsic rate (70 impulses/min) than the AV node (50 impulses/min)
• AV can take over if SA fails or transmission to AV is blocked
AP - Membrane potential changes soinside of cell become (+) relative
to outside
Fig 14-11
3) Conduction fibers (Bundle of His & Purkinje fibers)•Rapidly conduct (4m/s) AP generated by the pacemaker cells
•Cell-cell rate through gap junctions in only 0.4m/s•The heart consists of 2 syncytiums (atrium and ventricles)
connected by conduction fibers
Fig 14-9
Location Firing Rate at Rest SA Node (pacemaker) 70-80 APs/min
AV Node 40-60 APs/min Bundle of His 20-40 APs/min
Purkinje Fibers 20-40 APs/min
Autorhythmic Cells
•Fastest depolarizing cells drive all other cells
•Pacemaker = sets pace for entire heart
•Heart contraction called myogenic (trigger within)
•Contrast to neurogenic for skeletal muscle (trigger from nerve)
Sequence of electrical events that triggers a heartbeat
1
2
3
4
Fig 14-10AP initiated in SA
nodeSpreads
through atrial muscle
Internodal and interatrial pathway
AV node
Transmission slows down at the AV node by ~0-15s
Separator atrial & ventricle stimulation
AP transmitted through the AV node to the Bundle of His
Divides into L and R bundle branches
•AP enters a network of branches along the ventricle muscle: Parkinje Fibers
•Impulse travels through ventricle from apex towards valves
•Ventricles have coordinated contractions
Regulation of heart rate (hr) – both rate and flow are regulated•Heart rate affected by changes in rates of AP generated by pacemakers
SNS NE
PSNS AChVegus nerve
Cardiac nerve
(acetylcholine)
•Pacemakers get direct input by autonomic
nervous system
•SNS & PSNS have opposite effects
•Note: SNS has more connector & myocardium (more force effects then
PSNS)
•Acts on SA and AV nodes via B-adrenergic receptor
to increase hr
•SA and AV nodes via M2 muscarinic receptor to
decrease hr
•Predominant factor in setting resting heart at
70bpm (rate without inputs = 100 bpm)
Hormones (e.g. epinephrine) can affect heart rate•Increase hr via same mechanism as SNS
Temperature: •directly alters the intrinsic rate of the SA node, changes hr
by 156 bpm/oC•e.g. 1 degree fever hr is ~85bpm
Regulation of heart rate (hr):
Regulation of stroke volume•Volume ejected by ventricles with each heartbeat = stroke
volume (SV)•SV= end diastolic volume (EDV) – end systolic volume (ESV)
Ejection fraction =
p438
SVEDV
SV
EDV
ESV
EDV (ventricle filled) = 130mL
ESV (ventricle emptied) = 60mLSV (volume ejected) = 70mL
If EDV ↑ then SV ↑
If ESV ↑ then SV ↓
~67% at rest, increases during exercise
~33% of blood still left in heart
Biology 2A03Lecture 13
Circulation and Kidney I
due to increased CO & large decrease in skeletal muscle Resist.
- active hyperemic Beta2-vasodilation
due to large increase in Heart Rate
& small increase in Stroke Vol. due to increased SNS, Epi,
Temp, and decreased PSNS
Starling Law effects & *increased contractility (SNS, epi)
minor increase in MAP = CO*TPR
skeletal muscle dilation greater than constriction in other areas
Summary of cardiovascular changes during mild exercise
increased pressure pulsatility mainly due to increased SV
Despite all these complex changes, the MAP did not change very much -this reflects the
homeostatic role of the baroreceptor reflexes.
The role of the baroreceptors (sensory receptor neuron) is to keep systematic MAP as close to
100mm of Hg as possible.
Baroreceptor reflexes are the most important short term regulators of MAP (seconds to minutes)
The arterial baroreceptors continually monitor the systemic MAP and inform the cardiovascular control
centre in medulla of brain.
– Baroreceptors = stretch receptors
– Arterial baroreceptors • High pressure
baroreceptors• Sinoaortic
baroreceptors– Location
• Carotid sinusVia closso-pharyngeal nerves
(IX) (aka afferent branches)
• Aortic archVia vagus nerves (X) (aka
afferent branch)
X/IX refers to nerve designations, don’t need to
know them.
Fig. 15-26See Fig 15-27
Effect => stimulation of the autonomic nervous system.
The level of MAP is continually “coded” as A.P. frequency sent by the arterial baroreceptors.
Figure 15.25
A decrease in blood pressure (far right) gives less of a stretch, giving a decrease inThe rate of firing, opp holds true for middle (more stretch => increased RoF.
This is “reset” at a higher level in hypertension.
Baroreceptor (~30s reponse)
Note: remember this & previous slidefor tilt table experiment in next lab
– Following hemorrhage:
• Baroreceptor reflex • Increase in
sympathetic activity
• Decrease in parasympathetic
activity
– Result • Reflex
compensation
Figure 15.27
Efferent pathways of the Baroreceptor Reflex
Sympathetic nerve goes to pacemaker cells to increase
heart rate, and to heart muscles to increase the
rate of contraction.
Figure 12.59Baroreceptorreflexes
Baroreceptor reflexes also facilitate a short term
partial restoration of blood plasma volume by
reabsorbtion of fluid from interstitial space and
lymph
Long-term reg. of MAPhappens at the kidney.
• Blood plasma volume
• All ions (e.g Na+, Cl-, HCO3-, K+, Ca2+, Mg2+,SO4
=)
• Acid-base status (pH of the body fluids)• Excretion of all metabolic wastes – urea, uric
acid, ammonia, etc.• Excretion of all foreign substances
• Retention of all valuable substances• Red blood cell levels - via EPO
• Production of the renal hormones• Gluconeogenesis from amino acids during
fasting
Kidney Function = Renal SystemChapter 19
Regulates:
kidney
Ureterundergoes wavelike
contractions of smooth
muscle.
Bladder smooth muscle with gap
junctions.
urethra
THE URINARY SYSTEM
Fig 19-1NOTE – all smooth muscles have gap junctions
Detrusor (smooth) muscle
ureters
Internal urethral sphincter
External urethral sphincter
THE URINARY BLADDER
Filling:•P.S.N.S = inactive
•S.N.S. = active•Somatic N.S. = active
involves co-operation of P.S.N.S , S.N.S. & Somatic N.SPeeing:
•P.S.N.S = active•S.N.S. = inactive
•Somatic N.S.= inactiveFig 19-21
PSNS control
SNS control (we control it consciously)
Skeletal Muscle under Somatic N.S control.
MICTURITIONREFLEX
Fig 19-22urination
Biology 2A03
Lecture 14
Kidney II
medulla cortex
ANATOMY OF A KIDNEY
Fig 19-2Read pages 579-584
Cortex
Medulla
t
t
t
t
pyramid
renalpelvis
Capsule (outertissue)
ureter NephronUses circulation
To filter waste
Lots of nephrons allows for easier/greater volume offiltration.
Nephron = basic unit of structure & function in the kidneyNephron = an individual kidney tubuleand its associated blood supply
• Each renal pyramid contains 100,000-200,000 nephrons• 8-15 pyramids per kidney, each with separate branches
of renal artery and renal vein• 1.0 -1.5 million nephrons per kidney x 2 => 2-3 million
nephrons total in your waste filtration system…lots of filtration, similar to arteries…small, but large surface area when combined with others
• by the time the urine leaves nephron, it is fully formed (processed so that it only contains wastes, nutrients have been removed and sent for processing)
• we can understand urine formation by understanding the fuction of a single nephron.
Fig 19-3
Efferent Arteriole
Afferent Arteriole
Distal convoluted tubule
Common collecting
duct
Glomerulus inside of Bowman’s Capsule
Proximal convoluted tubule
Proximal tubule
Loop of Henle…loops into themedulla…important point, will be
covered later.
Afferentarteriole
Efferentarteriole
Fig 19-6
Glomerularfiltration
SNS input to both
To Renal Vein
GFR = GlomerularFiltration Rate
Peritubular CapillaryBed (reabsorbtion of
Stuff back into the blood)
Vasa Recta
This system uses Capillaries to help filter
stuff in and out
Nephron Components - Blood side
- essentially two capillary beds in series, joined by an arteriole = “portal system” • Afferent Arteriole = 1st important site of vasular resistance control
• Glomerulus = 1st capillary bed, site of formation of primary urine by filtration (bulk flow of protein free plasma)• Efferent Arteriole = 2nd important site of vascular resistance
control
• Peritubular Capillary Bed & Vasa Recta = 2nd capillary bed, site of reabsorbtion (selective transport from tubule to IF, recovery) & secretion (selective transport back to tubule, waste disposal)
• Filtration, reabsorbtion, and secretion are the 3 basic processes by which the urine is formed
Nephron Components - Urine or Tubule side- tubule is essentially a single winding tube along which the urine flows & gets progressively modified
• Bowman’s Capsule = receives the primary urine by filtration from the glomerulus
• Proximal Convoluted Tubule = largest part, quantitatively the most important for reabsorption and secretion.
- 65% of Na+, Cl-, H20 reabsorption occur here (fixed value)- 95-99% of everything else is reabsorbed here (fixed value)- > 90% of secretion occurs here for most substances• Loop of Henle = critical part of the counter-current system
for concentrating urine & conserving H20.
- 20 % of Na+, Cl-, and H20 reabsorption occur here (fixed value)
- *Fixed value = can’t be modified by actions of hormones.
• Distal Convoluted Tubule (DCT) - 2nd largest part of nephron• Common Collecting Duct (CCD) - drains many nephrons into the
renal pelvis & is the other critical part of the countercurrent system- together, the DCT & CCD account for ~15% of Na+, Cl-, and H20
reabsorption (variable value => responsive to hormones)- variability occurs because these are sites of hormone action,
controlling reabsorption (& also secretion)- key hormones are aldosterone & ADH (antidiuretic hormone =
vasopressin), also atrial natriuretic hormone & angiotensin II- the DCT & CCD are the major sites of K+ secretion ( if potassium
levels are high, heart may experience trouble functioning properly)
Nephron Components - Urine or Tubule side
The 3 Basic Exchange ProcessesPeritubular Capillaries
Afferent Arteriole
1. Glomerular Filtration passive due to Starling-Landis forces.
2. Tubular Reabsorption
3. Tubular SecretionMainly by active transport
Excretion
Efferent Arteriole
12 3
A Simplified Model of Nephron Function
(a) Many active transport processes for ions and nutrients.
(b) Passive diffusion (ions/nutrients) and osmosis (H20)
(c) Starling-Landis Forces.
Fig 19-7
Plasma may contain thingsthat cannot go through the
Bowman’s capsule therefore tubular secretion =>
1. Glomerular Filtration• A volume equivalent to 20% of the plasma flowing
through the glomerular capillaries is filtered, forming the primary urine collected into Bowman’s capsule.
• This “filtrate” contains a representative sample of everything in the plasma except proteins (& protein-bound substances)
- M.W cutoff ~ 68,000; smallest plasma protein = albumen ~ 69,000 (albumen is too large to be filtered/secreted)
• Glomerular Filtration Rate = GFR = 180 Litres/day
• Entire plasma volume of the body is converted to primary urine every 25 minutes!
• > 99% of the filtrate is subsequently reabsorbed in the tubule
• “A shotgun strategy” for excretion (process everything initially, then recover useful contents)
• a fraction (20%) of everything in plasma is filtered
- valuable substances are selectively reabsorbed- wastes, foreign substances are not reabsorbed• Therefore the kidney can excrete virtually any
waste or foreign substance
1. Glomerular Filtration
Filtration fraction
Plasma flow = 625 mL GFR = 125 mL Filtration fraction = 125/625
= 20%
Afferentarteriole
Efferentarteriole
180 L filtered /day but only 1.5 L of urine excreted / day
Fig19-9
625 mL/min
~500 mL/min
125 mL/min
Fig 19-8
Bowman’s capsule
Basement membrane
Slit pore
podocyteFoot processes
Glomerulus membrane(filtration barrier)
Endothelial cell
Epithelial cell (podocyte)
fenestration
Fenestrations/slit poresAllow for movement of
Proteins under a certain Specified M.W. (68K Da)
Glomerular capillary
Bowman’s Capsule
Filtration Barrier at M.W ~ 68,000
• podocyte slit pores• basement membrane
matrix - negative charge repels proteins• endothelial fenestrae
Filtration Barrier
Lecture 15
Kidney III
Fig 19-8
podocyteFoot processes
fenestration
Glomerulus membrane(filtration barrier)
Endothelial cellBasement membraneEpithelial cell (podocyte)
Slit pore(between podocytes)
Renal corpuscle
Filtration slit
Glomerular capillary
Bowman’s Capsule
Filtration Barrier at M.W ~ 68,000
• podocyte slit pores• basement membrane
matrix - negative charge repels proteins• endothelial fenestrae
Filtration Barrier
1. Glomerular Filtration
NFP = (PGc + piBC) – (PBC + piGC)
= (60 mm Hg + 0 mm Hg) – (15 mm Hg + 29 mm Hg)
Starling -Landis Forcesinvolved in glomerular filtration
Fig 19-9Recall PCAP = 38 mm Hg for a systemic capillary
PGC
PBC
PiGC
PiBC
= + 16 mm Hg (net positive pressure outwards)
Constrict aff. arteriole? = increase aff. resistance =
decrease NFP = decrease GFP
Constrict eff. arteriole? = increase eff. resistance =
increase NFP = increase GFP
Balance of aff. and eff. resistance is very important in controlling a proper equilibrium of flow and
filtration, and balancing the GFR.
Level of MAP is also very important in controlling GFR
Afferentarteriole
Efferentarteriole
PGC
3. Tubular Secretion• A relatively few substances (~20) which are often present in great excess
are actively transported into the urine from the blood • e.g. H+, K+, urea, ammonia, uric acid, antibiotics, PAH • occurs mainly in proximal convoluted tubule, except for K+
2. Tubular Reabsorption• All “valuable” substances (a very large number) are reabsorbed from the
urine into the blood by a combination of active and passive mechanisms.
• e.g. ions, H20, amino acids, fatty acids, vitamins, hormones.
• occurs mainly in proximal tubule, but variable reabsorption of H20, Na+, Cl-, and urea in DCT & CCD determines final urine volume and composition
• because of this active transport work, kidneys can account for 20% of BMR of the whole body.
Na+
Cl-
K+
Ca2+
HCO3-
H2OGlucose
Amino acidsVitamins
Ureacholine
H+
Na+
Cl-
K+
Mg2+
Ca2+
Na+
K+
Cl-
K+
Ca2+
H+
HCO3-
H2OUrea
K+
H+
NH4
H2O
H+
K+
Ca2+
Na+
Cl-
H2O
medullaryosmoticgradient
CCD
DCT
Some Patterns of Renal Handling
Filtered & additionallysecreted so totally
cleared from blood - e.g. PAH = Para-
amino hippuric acid
Filtered & largely but not completely
reabsorbed - e.g. H2O, ions, etc
Filtered & completely and reabsorbed, ie most
nutrients, such as glucose, amino acids
Reabsorption Barrier
Active transport of Na+ and glucose co-transport
Plasma membrane only a barrier for macromolecules
Tubule epithelia the 1º barrier for reabsorption proximal tubules have more microvilli
than either the DCT or CCD.
Reabsorption Barrier
Tight junctions between epithelial cells restrictparacellular transport (i.e. forces diffusion THROUGH the cells. Proximal tubules have leaky tight junctions, tighter
junctions found in DCT and CCD, ie Proximal tubules have more SA and looser tight junctions => ^^ transport
(selective).Proximal tubules also have higher mitochondrial content
due to many active transport processes
The same barriers must be crossed for secretion
See Fig 19-17
Excretion Rates
Filtered load
Excretion = Filtered (F) + Secreted (s) – Reabsorbed (R) = GFR*[x] + S – R [plasma content of object X being examined]
Analysis of Renal Function• Excretion Rate = Ex = [X]u * UFR
• Clearance Rate = Cx= the rate (ml/min) at which plasma is “totally cleared” of a substance by the kidney (eg all K+ is removed)
Cx = ([X]u * UFR / [X]p)
• If X is a substance which is totally cleared from the plasma (e.g. PAH) –
then clearance rate is total, Renal Plasma Flow Rate• e.g.CPAH=(450 microg/mL + 2 mL/min)/1microg/mL
= 900 mL/min (amount of plasma which would contain 450 microg of PAH)
Excretion Rate
Conc in plasma
Analysis of Renal Function
• If X is a substance which is freely filtered at the glomerulus (like virtually everything else in plasma), but neither secreted nor reabsorbed, then its clearance rate is the glomerular filtration rate (GFR) - e.g. inulin
Cinulin = GFR=
• GFR is 20% of renal plasma flow (20% of
900ml/min is 180ml/min)• Filtration rate of x =
Biol 2A03Lecture 16
Renal IV
Analysis of Renal Function• Excretion Rate: Ex = [x]u x uFR• Clearance Rate: Cx= the rate (mL/min) at which plasma is
“totally cleared” of a substance by the kidney
Cx = [x]u x uFR Excretion Rate [x]p Conc. in plasma
• If x is a substance which is totally cleared from the plasma (e.g. PAH) then the clearance rate is total renal plasma flow rate
CPAH= 450 ug/mL x 2mL/min = 900 mL/min 1 ug/mL
microgramAmount of plasma that would contain 450ug of
PAHp = plasma
u = urine
uFR = urine flow rate
Analysis of Renal Function
• If X is a substance which is freely filtered at the glomerulus (like virtually everything else in plasma), but neither secreted nor absorbed, then its clearance rate is the glomerular filtration rate (GFR) e.g. insulin
• Cinulin = GFR= 90 ug/mL x 2 mL/min = 180 mL/min 1 ug/mL
• GFR is 20% of renal plasma flow (20% of 900 mL/min is 180 mL/min)
• Filtration rate of x = [x]p x GFR
Analysis of Renal Function
• CRx= clearance rate of x
• CRx= = clearance rate of x = Cx .
GFR Cinulin
• CRx= excretion rate of x = [x]u x uFR
filtration rate of x [x]P x GFR
CRx tells you quantitatively how a substance is handled by the kidney
• CRx = 1.0 - substance is neither secreted nor reabsorbed on a net basis
• CRx > 1.0 – substance is net secreted e.g. PAH
• CRx < 1.0 – substance is net reabsorbed e.g most ions and nutrients
Typical values:
• water - CRH2O = 0.01 99% reabsorbed
• sodium CRNa+ = 0.005 99.5 % reabsorbed, only 0.5% excreted
• Urea CRurea = 0.56 44% reabsorbed
• potassium CRK+ = 0.01 – 2.0 – varies from strong reabsorption in K+ - depleted individuals to strong secretion in K+ - vegetarians
Regulation of NaCl and H2O by the Kidney
- 65-70% of Na+ and H2O reabsorbed by Proximal tubule (PT), No hormonal regulation.
- ~15% of Na+ and H2O reabsorbed by Distal Convoluted Tubule (DT) and Common
Collecting Duct (CCD), Varied by hormonal regulation.
- DT and CCD have 2 cell types: 1) Principle cells are the site of Hormonal regulation of
Na+ and H2O reabsorption. 2) Intercalated cells are involved in acid-base balance.
- Cl- follows Na+ passively therefore we will focus on Na+ reabsorption.
The Medullary Osmotic Gradient
aquaporins
1. Proximal tubule and cortex (leaky tight junctions)2. make descending limb permeable to H2O
3. Ascending limb but actively transport ions
H2O Reabsorption
Cortex
Medulla
Regulation of NaCl and H2O by the Kidney
Collecting Duct •Water is reabsorbed passively (osmosis),
generates a [ ] gradient
•Depends on O.P (1. Loop of Henle, 2. NaCl reabsorption)
•Counter-current multiplier system (loop of henle) serves to create high osmotic
pressure in ISF and blood vessels through which the CCD runs
•Tubular fluid is hypo-osmotic
•Water reabsorption is regulated by the permeability of DDT and CCD
100 mOsM
300 mOsM
1400 mOsM
O.P
onto bubble
H2O Reabsorption – DT/CCD Impermeable
100mOsm
100mOsm
100mOsm
100mOsm
100mOsm
300mOsm
1400mOsm
600mOsm
1000mOsm
Regulation of NaCl and H2O by the Kidney
•No water reabsorption (in this scenario)
•Urine has low osmolarity and high volume
100mOsm
300mOsm
1400mOsm
600mOsm
1000mOsm
H2O Reabsorption – DT/CCD Permeable
Regulation of NaCl and H2O by the Kidney
300mOsm
600mOsm
1000mOsm
1400mOsm
water
water
water
water
•water reabsorbed (in this scenario)
•Urine has high osmolarity and low volume
H2O Reabsorption – Regulation by ADH Regulation of NaCl and H2O by the
Kidney
•Ant diuretic hormone (ADH), a small peptide also known as vasopressin, released from the posterior pituitary gland by neurosecretory cells that originate
in the hypothalamus
Low O.P High O.PADH
ADH receptorAquaporin 2
water
Aquaporin 3
cAMP/PKA pathway
waterwater
Lumen ISF Plasma
H2O Reabsorption – Summary of ADH Action
1. ADH binds receptor on basolateral membrane of principal cells.
2. Receptor activates cyclic adenosine 3’, 5’ monophosphate / Protein Kinase A (cAMP /
PKA) pathway.
3. PKA stimulates production of Aquaporin 2 and insertion of Aquaporin 2 into the apical
membrane of principal cells.
Result: increased permeability of DDT/CCD to water leads to increased reabsorption of water
Regulation of NaCl and H2O by the Kidney
Ethanol (inhibits this)
Longterm Regulation of MAP
•Dehydration
•Brain shrinkage HANGOVER
Na+ Reabsorption and its Regulation by Aldosterone -Na+ reabsorption is coupled to K+ secretion
-Aldosterone is a steroid hormone released from the adrenal cortex in response to low
NaCl in ECF
Regulation of NaCl and H2O by the Kidney
[Na+] [Na+][Na+]
Na+
K+
Na+
K+
K+Na+
receptor
aldosterone
Na+/K+ ATPase
(3 Na+ in/ 2 K+ out
[K+] [K+] [K+]Passive Active
Na+ Reabsorption – Summary of Aldosterone Action
1. Aldosterone diffuses across basolateral membrane and binds to a cytoplasmic
receptor in principal cells.2. Receptor activation leads to: a) openning of
Na+ and K+ channels in apical membrane. b) synthesis of more Na+ and K+ channels for
insertion into apical membrane. c) synthesis of more Na+/K+ATPases for insertion into
basolateral membrane.
Result: increased permeability of DDT/CCD to Na+, increased NaCl reabsorption and K+
secretion
Regulation of NaCl and H2O by the Kidney
Regulation of NaCl and H2O by the KidneyInteractions between ADH and Aldosterone
-Since H2O and Na+ control systems are at least partially separated, humans can achieve
independent NaCl and H2O balance over a wide range of intakes. (0.5 to 25L/day H2O and 0.05 to
25g/day NaCl) Plasma Hormone Levels
Urine Flow Rate Urine [NaCl]
Low ADH / Low Aldosterone Highest Quite high
High ADH / High Aldosterone Lowest Quite low
Low ADH / High Aldosterone Quite high Lowest
High ADH / Low Aldosterone Quite low Highest
Biology 2A03Lecture 17
Kidney cont… & Neuro I
Regulation of NaCl and H2O by the KidneyInteractions between ADH and Aldosterone
-Since H2O and Na+ control systems are at least partially separated, humans can achieve independent
NaCl and H2O balance over a wide range of intakes. (0.5 to 25L/day H2O and 0.05 to 25g/day NaCl)
Plasma Hormone Levels
Urine Flow Rate Urine [NaCl]
Low ADH / Low Aldosterone
High ADH / High Aldosterone
Low ADH / High Aldosterone
High ADH / Low Aldosterone
Highest Quite High
Lowest Quite Low
Quite High Lowest
Quite Low Highest
Two other hormones also control nephron function:
2. Angiotensin II - part of Renin-Angiotensin System (“RAS”)
1. Atrial Natriuretic Hormone (“ANH, ANF, ANP”) - released by walls of atria in response to high venous
filling pressure(usually indicative of high blood volume associated with
high NaCl content in body)ANH increases NaCl and H2O excretion by raising GFR &
inhibiting active Na+ readsoption.
Angiotensinogen is a large plasma protein, originally produced in the liver, and is ALWAYS present in large
amounts in the plasmaRenin is an enzyme released by juxtaglomerular (see Fig
19-5) of the kidney in response to low NaCl content in body. Renin cleaves angiotensinogen to angiotensin I.
Angiotensin Converting Enzyme (“ACE”) is located in capillary endothelia, especially in lungs, & cleaves
angiotensin I to angiotensin II.
Fig 19-5
Low Body NaCl
Angiotensin II - Multiple Effects:•Stimulates aldosterone from adrenal cortex, thereby
increases Na+ reabsorption.
•Directly stimulates Na+ reabsoption itself • Constricts most systemic arterioles, thereby raises
MAP•Yet it reduces GFR (afferent R increases)
•Consequences: increases NaCl & H2O retention, increased blood volume & increased MAP.
Fig. 20-15
See Fig 20-23 for overviewof response to hemorrhage
Changes in GFR can be used to regulate water loss
Control of GFR by constriction and vasodilation
NOTE: the patterns in change in flow is importantand most likely will be on the tests.
Controlled by hormone action
Neurophysiology I
Function of the Nervous system
- collects sensory information from specialized cells (sensory receptors).
- 2 cell types: neurons, glial cells
- processes sensory information (integration).
- transmits appropriate information (response) to effector organs (muscles, glands).
Organization of the Nervous System
-2 Parts:
1) Central Nervous System (CNS): spinal cord and brain, area where integration occurs = decision
making 2) Peripheral Nervous System (PNS):
everything outside the spinal cord and brain (except enteric nervous system – gastrointestinal tract)
Conducts information from external and internal sensors to the CNS (afferent division) AND from the CNS to effector organs that are usually muscles and
glands (efferent division).
Function of PNS:
Efferent division of PNS-2 Parts:
1) somatic nervous system: motor neurons that regulate skeletal muscle contractions. Only
Excitory information which causes voluntary action.
2) autonomic nervous system: neutons that regulate internal organs and structures ( smooth
muscle, cardiac muscle, glands, etc)Both excitatory and inhibitory information.
Involuntary activity.
Divided into sympathetic (SNS) and parasympathetic (PSNS) nervous systems which usually have opposite
effects on effector organs.
Organization of the Nervous System
Figure 8.1, page 211.
2 Cell Types: (neurons and glial)
A) Neurons
-Many different types and anatomies (ie: afferent sensory neurons, interneurons, efferent motor
neurons), in humans they can be 1millimetre to 1 metre in length.
-Make up 10% of cells of the nervous system.
-Basic functional unit.
- Excitable cells: can produce rapid electrical signals “Action Potentials” (APs) = waves of electrochemical
energy that pass along the length of the neuron. Use AP’s to transmit information rapidly over long
distances.
-Can be structurally and functionally classified.
Sensory/receptor
Effector organs
3 Functional classes of Neurons, Fig 8.4, pg 215
Structure of a Typical NeuronDendrites: numerous small branches, receive most of
incoming information from other neurons via
synapses. Results in Graded Potentials (GP’s).Cell body or soma: contains
most organelles, metabolic functions. .Axon hillock: trigger zone, fires APs as a result of summation
of GPs. Site of most integration .Axon: thick process, rapidly conducts outgoing
information coded as AP’s Terminals: make synapses
with other neurons or effector cells.
Signal Direction
Two neurons communicating:
Synapse: neurotransmitter. Signal passed from presynaptic
neurons to post synaptic neurons
.
( Fig 8.2, pg 212)
Biology 2A03Lecture 18
Neurophysiology II
Sensory/receptor
Effector organs
1. Afferent neuron (input)
2.interneurons
3.Efferent neuron (output)
3 Functional classes of Neurons, Fig 8.4, pg 215
3 Structural Classes of Neurons, Fig 8.3, pg 214
2. Bipolar: 1 axon, 1 dendrite, generally
sensory neurons (olfaction = smell).
3. Pseudo-unipolar: subclass of bipolar, majority of sensory,
neurons, dendritic processes (through the peripheral axon)
transmits action potentials.
1. Multipolar: most common neuron,
multiple projections (1 axon, the rest are
dendrites).
2 Cell Types:
B) Glial Cells
- supportive, nutritive, & protective cells of the nervous system, but NOT directly involved in signal
transduction.- represent 90% of the nervous system.
- provide nutrients and remove wastes to/from neurons
- provide electrical insulation (“myelin sheath”) which prevents cross-talk & greatly increased A.P.
velocity- provide protection against toxins etc. - contribute to
“blood-brain barrier”
- provide homeostatic regulation of ECF around axons & synapses- e.g. remove excess K+ and
neurotransmitters
Myelin Sheath
Schwann Cells are the most numerous glial cells
in in the P.N.S.
Oligodendrocytes are the most numerous glial
cells of the C.N.S. Myelin sheath: multiple layers of
myelin lipid formed by plasma
membranes of glial cells wrapped
around axons like a jelly-roll. Functions
as insultation for the signal being
transmitted.Myelin sheath is regularly interrupted at
the Nodes of Ranvier (a.k.a. just Nodes)
Nodes
Schwann cell
Axon
oligodendrocyte
Oligodendrocytes and Schwann Cells insulate against “cross talk”, but their most important function is to
facilitate a high conduction velocity for AP’s.
These cells insulate > 99% of the distance along the axon. Nodes of Ranvier occupy < 1% of the total
distance.Kyelin sheath insultates the diffusion of ions, reducing
interference in the signal being sent.APs are rather slow events involving diffusion of ions. However, APs can leap at the speed of electricity (~ instantaneous) from one Nodes ot the next Node by
saltatory propagation.
AP conduction velocity may be accelerated up to 1000x by saltatory propagation.
Myelin Sheath
3 Basic Principles of Membrane Potentials
1. At a “macro” level, there are equal numbers of + and – charges in biological solutions (electrical
neutrality), though this does NOT mean that there is no transfer of ions…it is simply balanced by an equal
transfer of +/-.2. At a “micro” level, membrane potentials result from minutes charge imbalances across membranes e.g. in AP < 1 out of every 100,000 Na+ and K+ ions actually
moves.
Note: All cells have a “membrane potential” BUT we’ll focus on the membrane potential of neurons.
A difference in “electric charge” or voltage across the membrane of cells.
3 Basic Principles of Membrane Potentials
3. Most membrane potentials are associated with 3 factors:
(i) Unequal distribution of ions across membranes.
(ii) An active transport mechanism which maintains/restores this unequal distribution - e.g.
Na+/K+/ATPase pumps.
(iii) Differential permeability of the membrane to different ions
Note: for ions, the electrical analogue of permeability is Conductance (G) which is essentially the inverse of
Resistance (i.e. how much flows, not how the flow is impeded).
The Resting Membrane Potential
Inside Neuron
OutsideNeuron
3 Na+
2 K+
Electrogenic Na+/K+ -ATPases i) move more +’ve
charge outside the cell. ii) move K+ and Na+ against
the gradient to maintain an unequal distribution across
the membrane.
-70mV
RESULT: negative resting membrane potential.
Na+
K+
GK+ >> GNa+ :this means that more K+
leaves the cell than NA+ entering the cell. This
differential permeability of the membrane to
K+/Na+ leads to more +’ve charge leaving the
cell.
K+
K+
Na+
Cl-
Na+
A-
(Organic anions)
Electrical Potential
Equilibrium Potentials and Nernst Equation
(Chapter 4)
- predicts the membrane potential (EM) if the unequal ion concentrations are fixed & the membrane is
permeable only to the ion being considered.
- predicts the membrane potential (EM) necessary to sustain the unequal distribution of that ion at
equilibrium - i.e. the point of balance between the electrical and concentrational forces on that ion.
- The Nernst Equation looks at only one ion at a time.
Equilibrium Potentials and Nernst Equation
- Most importantly, the difference between Nernst Equilibrium Potential (EN) and the actual
Membrane potential (EM) represents the net driving force on the ion in question. So the further
away that EN is from the EM, the greater the driving force for the diffusion of that ion.
**Note: The actual membrane potential (EM) is determined by simultaneous permeability to several
ions. So, Nernst Equation cannot calculate the actual membrane potential.**
Equilibrium Potentials and Nernst Equation
Nernst Equilibrium Potential (EN) for K+:
EK+ = 61 log [K+]o [K+]i
= 61 log[4mM] [140 mM] = -94
mV Nernst Equilibrium Potential (EN) for Na+:
= 61 log[145mM] [15 mM] = -60mV
Nernst Equilibrium Potential (EN) for Cl-:
= - 61 log[110mM] [5mM] = - 80 mV
The Nernst Equation: (calculation of equilibrium potential)
EIon = - 61 log[Ion]outside [Ion]inside
Made from 4 constants (the -61)
Equilibrium Potentials and Nernst Equation
- Na+ unequal distribution is a long way from equilibrium. Compare EM (-70 mV) with ENa
+ (+60 mV).
Driving Forces for Diffusion of ions:
- K+ and Cl- unequal distribution across membrane are close to equilibrium.
Compare: EM (-70 mV) with EK+ (-94 mV) and Ecl- (-80 mV).
- Therefore, greatest driving force for diffusion of Na+ (important for APs).
Note: by Nernst equation, -61 mV can sustain a 10-fold concentration difference because log 0.1 = -1.
Biology 2A03Lecture 19
Neurophysiology III
Recall:
Equilibrium potential (EN) via the Nernst Equation
EN = “A hypothetical value for the membrane potential at which the electrical driving force is equal and
opposite to the chemical driving force producing an electrochemical driving force of zero.”
If EN = EM for an ion then no electrochemical driving force acting on it to move in or out of the cell.
If EN ≠ EM there will be a driving force for that ion in or out of the cell depending on the direction and size of the
force.
(EN) for Na+:= 61 log [145 mM] = +60 mV [15 mM]
For example Na requires large positive outward directed electrical force (that is far from EM) to counteract a large inward concentration gradient. So Na has a large driving
force for inward movement.
EM = -70 mV
Changes in Membrane Potential: Terminology
Resting Membrane Potential
K+ Equilibrium Potential
Na+ Equilibrium Potential
Fig 8-9, pg 223
Cl- Equilibrium Potential
Depolarization (membrane
becomes more positive)
Repolarization (return towards
resting spot)
Hyperpolarization (membrane
becomes more negative)
Changes in ion permeabilities (Gi)
Fig 8.9, pg 223
Na+ Equilibrium Potential
Resting Membrane Potential
Cl- Equilibrium Potential
K+ Equilibrium Potential
If GK+ increases, EM will move towards – 94 mV, causing a hyperpolarization or repolarization.
If GNa+ increases, EM will move towards +60 mV = depolarization
If GCl- increases, EM will move
towards -80 mV, causing
hyperpolarization.
NOTE: in some cells ECl- = EM: “passively distributed”. In this
case changing GCl-has no effect on EM.
Increasing the permeability of a membrane for an ion will naturally cause an increased movement of that ion, causing a change in the membrane potential
Graded Potentials (GPs)
Relatively small changes in membrane potential caused by changes in GK+, GNA+ & GCl-that are due to opening (or closing) of specific K+, Na+, Cl- channels
in the cell membrane. The changes in GK+, GNa+, & GCl- , that cause GPs are
usually at synapses (neurotransmitter release) or at the peripheral ending of an afferent
neuron in response to stimulation of a sensory receptor. .GPs are therefore usually small (few mV or less)
and are conducted away from the site of origin by local flow of electrical current.
Local current flow is decremental: small change in membrane potential (GPs) becomes even smaller as it
moves away from the site of origin (different from AP’s, which are constant regardless of distance).
Axon Hillock
Fig 8.11, pg 226
Current Flow
Decrease in G.P. size with distance from origin is due to
decremental local current flow.
stimulus
Size of the arrows is proportional to the size of the GP’s in that area
Graded Potentials (GPs)
- opening of K+ or Cl- channels causes of membrane potential (inhibitory graded
potential).
- opening of Na+ channels causes depolarization of membrane potential (excitatory graded potential).
Why are they “Graded”:Because the size of GPs depends on the size of the
stimulus
So, a weak stimulus produces a small GP , a stronger stimulus produces a larger GP.
Fig 8.10, pg 225
Weak stimulus Strong stimulus
GP is “grade” in proportion to the strength of the stimulus.
Inhibitory, K+, Cl-Excitatory, Na+
Increased GK+, or GCl-
G.P’s at synapses on dendrites or soma are Post-Synaptic Potentials.
threshold threshold
At excitatory synapses, the neuro-transmitter generally opens both
Na+ & K+ channels ==> increased GNa+ & increased GK+==> net
depolarization“Excitatory Post-Synaptic Potential
“
At inhibitory synapses, the neuro-transmitter generally opens either K+ or Cl- channels ==> increased
GK+ or increased GCl-==> hyperpolarization
“Inhibitory Post-Synaptic Potential”
Single EPSP’s (e.g. +0.5 mV) are too small to raise EM to the threshold needed to intiate an Action Potential.
IPSP’s (e.g. -0.5 mV) move EM further away from the threshold.
EPSP’s & IPSP’s on dendrites & soma are conducted instantaneously to “initial segment” (axon hillock) by
decremental local current flow.
At the initial segment, process of summation occurs - threshold potential may or may not be reached ==>
decision = integration of the signal .
The closer the origin of a PSP to the initial segment, the larger it still is when it arrives theres.
Temporal Summation – PSP’s in quick succession add up.
Spatial Summation - PSP’s from different synapses add up.
The threshold potential is lowest ==> easiest to reach at the initial segment.
Fig 9-8
Illustration of Integration
Integration normally occurs here
GPs versus APs
Action Potentials (A.P.’s) result from large local changes of GNa+ & GK+ (GCl- does not usually change) which occur
once the threshold potential is passed by summation of G.P.’s.
A.P.’s obey the “all or none rule” (unlike G.P.’s).
A.P’s only occur in cells where there are “excitable membranes”==> membranes possessing voltage gated Na+ & K+ channels ==>
in addition to the regular leakage Na+ & K+ channels
Unlike G.P’s, A.P’s are short lasting (e.g. 1-3 millisecs) ==> as long as summated G.P.
stays above threshold potential, A.P.’s will keep firing, each separated by a
“refractory period” A.P.’s are large (eg 100-120 mV), and
are propogated long distances from the site of origin without changes in
size ==> “decremental conduction”
Fig. 6-19,p.170
Long-lasting summated G.P’s may hold membrane potential above threshold for a very long time - e.g. 100
msec ==>
Quiz # 2 – Monday March 5th
35 multiple choice questionsSame rooms as before – check LearnLink
80% new material, 20% from Lectures 1-11Bring: calculator, valid i.d.
Biology 2A03Lecture 20
Neurophysiology IV
Long-lasting summated G.P’s may hold membrane potential above threshold for a very long time - e.g. 100
millisec ==> A.P.’s will keep firing repetitively, separated by a Refractory
Period.
Sub-threashold GP’s AP “fires” as soon as summated GP passes the threshold
AP’s are a constantsize – obey an
“all ornothing rule”
AP’s are short-lasting relative to
GP’s
1. Resting potential- EM determined by leakage channels only: GK+ >> GNa+
1
1-2. EM increases due to G.P. & voltage-gated Na+ channels start to open. Na+
ions enter causing partial depolarization.22. At threshold potential, entry of Na+
ions exceeds exit of K+ ions= depolarization
Voltage-gated Na+ channels open explosively in a positive feedback loop:
GNa+ >> GK+ 3. So many voltage-gated Na+ channels
are open that EM surpasses 0 mV & enters overshoot phase. EM starts to
approach the equilibrium potential for Sodium (ENa+)
3
4. Before EM reaches ENa+, the voltage-gated Na+ channels automatically
close and voltage-gated K+ channels automatically open. GNa+ decreases and GK+ increases. K+ ions start to
exit. EM starts to return towards 0 mV (repolarization starts to occur)
4
GGNa+.
GK+
Direction of Na/K movement isNOT specified.
12
34
5-6. Exit of K+ ions greatly exceeds entry of Na+ ions resulting in
repolarization GK+ >> GNa+. EM decreases towards EK+
6-7. Hyperpolarization continues with EM close to EK+, because some
of the voltage-gated K+ channels remain open for some time.
(therefore a fairly high Potassium conductance for a while)
5
67
GGNa+.
GK+
Absolute Refractory Period (0.5 - 3 msec) - axon cannot carry another A.P. This corresponds to a period when
the voltage-gates Na+ channels are inactivated and are closed to the passage of Na+ & thereafter remain closed for a definite period==> “Na+ inactivation
period”. Relative Refractory Period (2-15 msec) - axon can carry
another A.P. but requires a greater than normal stimulus (e.g. G.P). This corresponds to a period when voltage-
gated Na+ channels can be re-opened but some K+ channels remain OPEN.
.The Refractory Period limits the frequency at which axons can
carry A.P.’s. - e.g. if Absolute Ref. Period was 2 msec, the maximum AP frequency would be about 500 AP’s/second.
Note: Na+,K+-ATPase continues to operate at a steady rate, correcting the very minor ionic imbalances that
result from A.P.’s
Voltage gated Na+ channels
GNa+.
Depolarization opens the activation
gate
~1 millisecond
Inactivation gate closes until EM returns to the
resting state.
In absolute refractory period most of the Na+ channels are open then inactivated and most of
the K+ channels start to open
In relative refractory more and more Na+ channels are able to be activated and many of the K+
channels start to slowly close
Absolute Refractory Period (no second AP possible,
regardless of the stimulus) No 2nd AP possible regardless of stimulus
Relative RefractoryPeriod
Stronger than normal stimulus needed for
an AP
Refractory period plays an important role in information coding
at the initial segment, because the further above threshold is the G.P., the greater the frequency, until the
absolute refractory period is reached.
At sensory receptors, the greater the intensity of the
stimulus, the greater the G.P., and the greater the frequency,
until adaptation occurs.
Information is coded as the frequency of A.P.’s
Increased stimulus duration
Increased stimulus strengthcausing more/faster AP’s
Suprathreshold stimuli = above the threshold stimulus
Time between AP directlyrelated to amplitude of GP
Fig. 8-18
Gradient Potentials
Gradient Potentials
Adaptation - a property of all sensory receptors
==> for any constantly applied stimulus, the frequency of A.P.s,
and therefore the perception of intensity, gradually declines with time.
==> Very complex - explained by electrochemical (e.g. channel closing), mechanical (e.g. gradual
deformation of receptor structure), and sometimes synaptic events.
Tonic receptors - adapt very slowly - generally associated with life-critical sensation - e.g. pain receptors, blood gas
chemoreceptors.
Phasic Receptors - adapt very quickly -generally associated with detecting changes in the environment - e.g. touch receptors, sound receptors. (are you wearing
clothes??)
Propagation of A.P. - in a non-myelinated axon
Local current flow (decremental) occurs at
the interface region, and brings the EM of the
neighbouring excitable membrane to threshold
==> this region now fires an A.P. ==> A.P. moves
along.
Local current flow also occurs at the other
interface, but the neighbouring region is in
Absolute Ref. Period, & cannot fire an A.P. ==>
A.P cannot move backwards.
The larger the axon diameter, the faster the propagation - e.g. squid
“giant axon” - Hodgkin & Huxley - Nobel Prize.
Biology 2A03Lecture 21
Neurophysiology V
Propagation of A.P. - in a myelinated axon- same mechanism, but
decremental local current flow is effective over longer
distances because of the insulation (current is not
dissipated in the membrane).
- Nodes of Ranvier are strategically placed so that
there is enough current remaining to bring the next Node to threshold potential.
- A.P. occurs only at Nodes, & “leaps” to next Node by
saltatory propagation ==> up to 1000-fold greater
velocity.
Only the vertebrates have myelinated axons and there are many advantages:
1. Much higher conduction velocity.
2. Saves space - axons can be much thinner, and more of them can be accommodated in the same
space.3. Metabolically much cheaper - because A.P.’s occur
only at Nodes, most of the voltage-gated Na+ & K+ channels,
and most of the Na+,K+ATPase molecules have been lost in the inter-nodal regions.Contrast (vertebrates):
non-myelinated “slow” post-ganglionic fibres
of SNS & PSNS.
Myelinated “fast”fibres of somatic nervous
system.
Diameter: Myelination: ConductionVelocity:
~2 um 1-2 layers
~12-25 um ~100 layers
0.5-1.0 m/sec
75-100 m/s
A.P travels down an axon until it reaches the terminal knob(s) where it activates a synaptic transmission.
Two types of synapses:(1). Electrical Synapses - direct cytoplasmic connections (gap
junctions) between pre-synaptic and post-synaptic cells.
A.P. passes directly from one cell to the next by local current flow.Common in cardiac & smooth muscle, but rare in nervous
system(< 1%) - defensive reactions only. Advantages: speed, low energetic cost (one way
directionality)Disadvantages: non-rectifying, no capacity for integration
(current can flow in both directions) (2) Chemical synapses - arrival of A.P. causes release of neuro-transmitter (n/t) from the pre-synaptic membrane
n/t diffuses across synaptic cleft, reacts with receptors on post-synaptic cell, which creates a G.P.
Common in nervous system (> 99%).
Advantages: rectifying (one way directionality), facilitates integration
Disadvantages: slow speed, high cost, can have delay of 0.2-2 millisec)
1-2. Arrival of A.P. opens voltage-gated Ca2+ channels Ca2+ enters
[Ca2+] = 10-3M[Ca2+] = 10-8M
3. Ca2+ activates docking of synaptic vesicles & release of n/t into synaptic cleft by exocytosis ( > 90% of synaptic delay). This involves contractile SNARE proteins.
4. n/t diffuses across synaptic cleft (10-20 nm - < 10% of synaptic delay)
5. n/t reacts with post-synaptic proteins receptor proteins, resulting in changes in GK+, GNa+ or GCl-
GP
Chemical Synapse
Termination mechanisms for synaptic transmission
6. n/t may be broken down by enzymes interspersed between receptor proteins - e.g. acetyl cholinesterase
(green blob) .7. n/t may be actively transported back into the pre-synaptic membrane for re-packaging into vesicles.
8. n/t may simply diffuse away from the synaptic cleft.
9. n/t may be actively taken up & metabolized by nearby glial cellsNote: Mechanisms 7, 8, & 9 will all decrease n/t
concentration in cleft, so n/t will dissociate from receptor proteins, thereby stopping the post-synaptic stimulation.
The “traditional view” was that n/t release followed the all or none low- that one A.P. always released the same amount of
n/t, and thereby created the same size GP at the post-synaptic membrane
We now know this is over-simplistic ==> many exceptions:
- auto receptors on pre-synaptic membrane may down-regulate subsequent n/t release.
- Multiple transmissions may temporarily exhaust synaptic vesicles of n/t.
- Desensitization or loss of post-synaptic receptor proteins may occur in response to multiple transmissions.
- upregulation of n/t release and/or post-synaptic receptor density may occur in frequently used or rarely used (!)
pathways.- Presynaptic inhibition or facilitation of n/t release may occur via
axo-axonic synapses.
===> frequency code is greatly modified at chemical synapses
Transmissions at axo-axonic synapses may modify n/t release
Presynaptic inhibition
Where two pre-synaptic neurons synapsewith each other before synapsing with the
axon
Neuron content is differentAnd so the neurotransmitters
May cause some kinda of Destructive interference.
The “traditional view” that synapses followed the All-or-None Law arose because all the early research on synapses
was done on one of the largest synapses - the neuromuscular junction - where this is true (Fatt, Katz, &
Miledi - Nobel Prize). Chemical synapse between somatic motor neuron &
skeletal muscle cell.
Many terminal processes embedded
in grooves in post-synaptic membrane.Contact area, amount
of n/t released, & receptor numbers are
all much greater than in neuron-neuron
synapses.Creates a GP large enough to produce an AP
So much acetylcholine (n/t) is released by one A.P in pre-synaptic neuron that one E.P.P. is +50 mV ===>
suprathreshold & fires A.P. in muscle cell.
The G.P on post-synaptic membrane (motor end plate) is called an End Plate Potential (E.P.P.).
One A.P in somatic motor neuron always normally elicits one A.P. in the skeletal muscle cell.
There is no capacity for integration at neuro-muscular junctionsbecause summation of G.P.’s does not occur there.
Biology 2A03Lecture 22
Cell metabolism I and II
2. Cellular respiration:e.g. C6H12O6 +6 H2O+ 6O2 ===>
12H2O + 6CO2 + 38 ATP
1. Gas exchange:movement of O2 from environment to cell (mitochondria) & movement
of CO2 in opposite direction
Two meanings of “respiration” (both correct)
Metabolic Pathways – ATP Synthesis
One of the major roles of metabolic pathways is to convert the energy in food (stored as fuel) to ATP to power cellular functions
ATP
ADP + Pi
ATP consumption
MovementMembrane transportMolecular synthesis
ATP production
Metabolic pathwaysCarbohydrates
Lipids (fats)Proteins
ATP can be produced by:
Substrate–level phosphorylation:(can occur in the absence of O2)
c) Oxidative phosphorylation(by definition uses O2 in mitochondria)
a) Glycolysisb) Kreb’s Cycle (TCA or citric acid cycle)
Oxidative Phosphorylation
Most important mechanisms of ATP production in mammals
Involves the reduction of O2 to H2O with electrons donated from reducing equivalents (NADH + H+
, and FADH2)
ATP production the result of:
1) Flow of e- through membrane-bound carriers
2) e- flow coupled with H+ transport from matrix to intermembrane space
3) Energy for ATP synthesis provided by H+ travelling back into the matrix via ATP-ase (F0F1)
See Fig 3-18Fig 3-19
-Electron transport chain – inner mitochondrial membrane
-Electrons from NADH +H+ and FADH2 pass along chain to lower E states until combined with O2
-Accompanied by proton transport to intermembrane space
-Protons reenter via ATPase and energy used to produce ATP (3 ATP / NADH and 2 ATP / FADH2)
Chemiosmotic model
Fig 3.19O2 .O2
-
-Heat and Reactive Oxygen Species (ROS) are other byproducts
Acetyl-CoA
Aminoacids
Fattyacids
Glucose
pyruvate
CO2PDH
Kreb’sCycle
CO2
CO2
NADH & FADH2
(reduced e- carriers)
ETC2H+ + ½ O2
H2OADP + Pi ATP
e-
e-e-
e-
e-
e-
e-
e-
e-
Stage 1 -Acetyl-CoA production
glycolysis -Pyruvate is derived from glucosevia glycolysis – 2 NADH + H+ formed
-Oxidized to acetyl-CoA bypyruvate dehydrogenase complex
(PDH) – 2 NADH + H+ formed
Stage 2 -Acetyl-CoA oxidation
Stage 3 - Electron transfer and oxidative phosphorylation
See Fig 3-21Fig 3-23
lactate
-acetyl groups from pyruvatefatty acids and amino acids
enterthe Kreb’s cycle
- 3NADH + H+ and 1FADH2 formedfor each pyruvate
-Electrons transferred from reducing equivalents to ETC
ATP yields from fuel sourcesAnaerobic glycolysis: (O2 not used)
10 enzymatic steps
Fig 3-22
Harmful waste product
Substrate level phosphorylation
Reduction-oxidation balance maintained(cytosol redux)
Aerobic metabolisms of:
Carbohydrates:
Glucose
Glycolysis + oxidative phosphorylation
2 pyruvate 2 ATP & 2 NADH + H+2Pyruvate 2 acetyl-CoA 2 NADH + H+
2 acetyl-CoA Kreb’s Cycle 2 ATP, 6 NADH + H+ & 2 FADH2
3ATP / NADH + H+, 2ATP / FADH2
Fats:β-oxidation produces acetyl-CoA for Kreb’s Cycle
See Fig 3-21
ATP
2+66
2+18+4
38 ATP
CO2
0 4 2
6 CO2
ATP
ADP + Pi
Short-term regulation
Phosphocreatine (PCr)ATP storesGlycogen
work
Long-term regulation
Oxidation of:Glucose and Glycogen
FatsProteins
ATP supply ATP demand
Homeostasis of muscle ATP
MovementMembrane transportMolecular synthesis
PCr + ADP + H+ ATP + creatine
Glucose + 2Pi + 2ADP
2lactate + 2ATP + H2O
Glycolysis
ATP hydrolysis and Phosphocreatine buffering
0-10 seconds
4 to 120 seconds
Oxygen is not involved
CPK
Short-term regulation of [ATP]
Oxidative metabolism
Glucose +6O2 + 36ADP + 36Pi
6CO2 + 6H2O + 36ATP
Carbohydrate oxidation
Lipid oxidation
Trioleate (C57H104O6) + 80O2
57 CO2 + 52H2O + 104ATP
2-5 hours!
Oxygen required
Respiratory exchange ratio (RER)Also called respiratory quotient
(RQ)= CO2 produced/ O2 consumed
= 6 CO2 / 6 O2 = 1.0 for carbohydrates
RER = 57 CO2 / 80 O2 = 0.75 for fat
2. Cellular respiration:e.g. C6H12O6 +6 H2O+ 6O2 ===>
12H2O + 6CO2 + 38 ATP
1. Gas exchange:movement of O2 from environment to cell (mitochondria) & movement
of CO2 in opposite direction
Fig. 17-2
Conducting zone -no gas exchange
between air & blood here
Respiratory zone
Anatomy of the respiratory tract
Biology 2A03
Lecture 23Respiration I
Fig. 17-2
Conducting zone -no gas exchange
between air & blood here
Respiratory zone
Respiratory bronchioles
Anatomy of the respiratory tract
Larynx
trachea
PrimaryBronchi
SecondaryBronchiTertiarybronchi
Alveolar sacAlveoli
Reinforced with cartilage & smooth
muscle –Prevents gas exchange
with blood
Little cartilage or smooth muscle –
allows gas exchange with blood
Fig. 17-3
Anatomical features
Differences in wall thickness important for gas exchange
30Mil alveoli – 100m2 Surface Area
Important Conducting Zone Functions• Larynx - phonation, guards entrance to trachea• Cartilage & smooth muscle provide great strength• Smooth muscle can constrict/relax, varying resistance to
air flow (bronchioles) SNS NE β2-adrenergic recepters - bronchodilation
PSNS ACH muscarnic receptors - bronchoconstriction
• Warms air to 37OC• Humidifies air to 100% R.H• Cleanses air by removing particles - mucus & cilia
provide the “mucus escalator”, macrophages ingest particles
Fig. 17-5
Respiratory Zone
Alveoli arranged in clusters
connected by pores whichallow equalization ofpressure in the lungs
Type I cells = epithelial layer
Type II cells = surfactant prod.
Macrophages= engulf foreign particles and pathogens
The Respiratory Membrane
T: Thickness A: Surface Area
K: Permeability Gas Constant
Diffusion rate = K x A x ΔPT
If K for O2 = 1, K for CO2 is 20
Respiratory Zone -site of O2 & CO2 exchange with blood
• Respiratory bronchioles• Alveolar ducts• Alveoli - 90%
10%
Lung Disease X
Alveolar surface is wet for gas exchange highSurface tension at air-water interface
Small size of alveoli (radius ~ 0. 1mm) makes them unstable
Alveoli have an innate tendency to collapse
Factors preventing alveolar collapse
• Alveolar pores equalize pressures between alveoli• Alveolar “Type II Cells” secrete surfactant (a protein +
phospholipid = detergent-like substance) which reduces surface tension by up to 90%
Note: “Respiratory Distress Syndrome” (RDS) in pre-mature babies is due to inadequate surfactant.
• Negative pressure outside the alveoli (-4 mm Hg, i.e below atmospheric pressure) in the intrapleural space helps to hold the alveoli open
• The other function of the intrapleural space is to serve as flexible, lubricated connection between the lungs and the thoracic wall.
Chest Wall and Pleural Sac
760mmHg
756mmHgor -4mmHgrel to atm
Parietal pleura attached to thorax
Intrapleural fluidMuscus, negative
pressure
Visceral pleura attached to wall of
lungs
Fig 17-9
Pneumothorax - a rupture which connects the intrapleural space to the outside atmosphere
elimintates the negative pressure breathing becomes ineffective and the lung
may collapse.
The flexible, lubricated connection created by the negative intrapleural space ensures that when thorax changes size during breathing, the lungs
will follow
Inhalation - active phase during both rest & exercise
Breathing Cycle
•External intercostal muscles pull ribs out & up
•Diaphragm shortens and moves down
ThoracicVolume
==> LungVolume
==> Negative pressure in lungs (i.e below atm pressure)
==> Air flows in from atmosphere
“thoracic suction”
Exhalation - passive phase during rest - slow
•Internal intercostal muscles pull ribs
•Abdominal muscles push “guts” in, thereby displacing diaphragm upwards
ThoracicVolume
==> LungVolume
==> Positive pressurein lungs (i.e above
atmospheric pressure)
==> Air flows out to atmosphere
Breathing Cycle
•Due to elastic recoil of thoracic & lung components
Exhalation - active phase during
**Prof Didn’t Cover This Slide. Maybe because it’s the same as the next slide**
•Internal intercostal muscles pull ribs in and down
•Abdominal muscles push “guts” in, thereby displacing diaphragm
upwards
Exhalation - passive phase during rest - slow
Exhalation - active phase during exercise - faster
•Due to elastic recoil of thoracic & lung components
Thoracic Volume
==> LungVolume
==>
Positive pressure in lungs (i.e above atm pressure)
==> Air flows out to atm
Thoracis pressure
Biology 2A03Lecture 24
Respiration II
** Next quiz 3 will cover primarily on “Respiratory System”
Mon. March. 12, 2007
SpirometryTechnique used to measure air volume
Tidal Volume = amount of air breathed in and out on a single breath ~ 0.5 LInspir. Res. = max. amount that can be inhaled above normal inhalation ~ 3 L
Expir. Res. = max. amount that can be exhaled beyond normal exhalation~1.5L
Resid. Vol. = amount left inside, cannot be exhaled even with max. effort ~ 1LInsp. Capacity = tidal volume + insp. reserve ~3.5 L
Functional Residual Capacity = exp. reserve + residual volume ~2.5 L
Vital Capacity = exhale maximally, then quantify max inhalation ~ 5.0 L
Total Lung Capacity = measured after maximal inhalation , ~ 6.0 L
Spirometer record
Minute Ventilation = total air flow into (and out of) the respiratory system per minute
Minute Ventilation = Tidal Volume * Breathing Rate
e.g. 6750 ml/min = 450 mL * 15/min.
Minute Ventilation = Alveolar Ventilation ?
This difference is because of Anatomic Dead Space which is air “stuck” in the conducting zone (always contain air and cannot be completely
emptied)
Alveolor Ventilation (VA):
VA = [Tidal Volume – Anat. Dead Space] * Breathing Rate
4500 ml/min = [450 mL – 150 mL] * 15/min.
Not equivalent to each other
Anatomical Dead Space-New air always get diluted by
old air- Old air has
less 02 & more CO2 than atm
in air
Fresh air comes in
Dead air gets pushed into
alveoli (stuck in anatomical dead space)
300 mL of “new” air is entering the 2500 mL functional residual capacity
which contains “old” air
Dilution Factor = (300 mL new + 2500mL old)/ 300 mL new = 9.3 times (of dilution factor)
==> Only ~10% replacement of alveolar air per breath at rest
==> Very constant O2 & CO2 levels in alveolar air at rest
==> Alveolar O2 is much lower , & alveolar CO2 is much higher , than in outside air
==> Alveolar O2 & CO2 values become closer to those in outside air during exercise when tidal volume increases & anatomic dead space remains unchanged
Minute alveolar ventilation = f x (VT – VD)
= (500ml x 12breaths) – (150ml x 12 breaths)
= 4200ml/min instead of 6000 without VD
150
2 x f = 8,400 mL/min. 2 x VT = 10,200 mL/min.
Better to increase tidal volume (Vt) than to increase beating frequency (f)
Table 17-1
Anatom. dead
space gets
pushed into
alveoli
Partial Pressure- a measure of the thermodynamic activity of gas molecules
diffuseGases dissolve according to their partial pressures, not
react necessarily according to their concentrations .
Dalton’s Law: Total pressure = sum of partial pressure
Room air: Total Pressure = PN2 + PO2 + PCO2 + PH2O
~ 760 mm Hg (torr) [barometric pressure] = 599 torr + 160 torr + 0.3 torr + (0 – 47 torr) [depending on relative humidity]
“torr” = in honour of Torricelli, inventor of barometer
In an air phase, Dalton’s Law can be applied directly
Partial Pressure = Total pressure * Volume (mole) Fraction
[Remember: equal moles of gases occupy equal volumes]
[1 mole of any gas occupies about 22.4 L @ STP (standard temperature & pressure]
Dry Room Air: PO2 = 760 torr * 210 mL O2/1000 mL air (21%)
= 160 torr
PCO2 = 760 torr * 0.39 mL CO2/1000 mL air (0.04%) = 0.3 torr
Note: the same principles apply to N2 (mole fraction = 79%), we generally pay little attention to N2 as it is an inert gas
In a fluid phase, situation is more complicatedPartial pressure of a gas in a fluid is equal to the partial
pressure of that gas in the air phase with which the fluid is in equilibrium (real or theoretical equilibrium)
PO2 = 160 torr
PO2 = 160 torr
Otherwise, to find the partialpressure, we need to apply Henry’s Law, & know both the concentration
& the solubility of the gas in the particular liquid
Henry’s Law = concentration of a dissolved gas is proportional to the partial pressure & to the solubility coefficient
Concentration = Partial Pressure * Solubility coefficient Partial Pressure = Concentration
Solubility Coefficient
*
*
* constant for a particular gas in a particular fluid under defined conditions
Water equilibrated with Room Air
PO2 = 7 mL O2/ 1000 mL water 0.044 mL O2/1000 mL water/torr
= 160 torrPCO2 = 0.40 mL CO2/1000 mL water
1.32 mL CO2/1000 mL water/torr = 0.3 torr
The capacity of water to hold O2 ( 7 mL/ 1000 mL water) is much lower than the capacity of air to hold O2 ( 210 mL/1000 mL air)
CO2 is about 30 x more soluble than O2 in water
The capacity of water to hold CO2 ( 0.40 mL/1000 mL water) is comparable to capacity of air to hold CO2 (0.39 mL/ 1000 mL air)
PO2 = 160 torr
PO2 = 160torr [O2] = 7 mL O2/ 1000 O2/1000 mL
[O2] = 210 mL O2/1000 mL Here, gases diffuse according to their partial pressures, not according to
their concentrations
Basic Components of gas transfer systems
1. Breathing movements
Continuous supplyto resp. surface
(convection)
2. Diffusion of O2 and CO2
across resp. epitheliumto blood.
3. Bulk transport
4. Diffusion of O2 and CO2
across capillary wallsto mitos in cells
Most of the total gas transport occurs by convection; diffusion is so slow that it is used only over very short distances - a
few um’s
PO2 drops with each step in O2 transport
PO2 at cell surface must be high enough for O2 diffusion to mitochondria.
The oxygen cascade
Biology 2A03
Lecture 25Respiration III
Alveolar partial pressures are very different from
outside air
PO2
160PCO2
0.3100
40
10040
10040
≥46≤40
All in mmHg(Torr)
4640
Partial pressures are the same in “venous” blood leaving the
systemic capillaries & entering the pulmonary capillary beds
4640
Memorize these key PO2 & PCO2
valuesSee Table 18-1
Systemic arteries
cells
Systemic veins
Alveolar air
Pulm veinsPulm arteryThe partial pressures are the same between compartments. Where the
changes occur are @ the alveoli and at the capillaries, where diffusion can
cause a change in the gas content of the blood. NEED TO KNOW THESE
PARTIAL PRESSURES!!
These areas of diffusion have significantly different pressures
compared to the previous compartment
O2Transport in the Blood
1.5% - physically dissolved in plasma and RBC cytoplasm.
98.5% - chemically combined with hemoglobin (Hb)
280 x 106 Hb molecules per RBC
4 O2 molecules bound per Hb molecules
~ 109 O2 molecules per RBC ~ 5 x 109 RBC’s per mL of blood
~ 5500 ml blood per person
~ 3 x 1022 O2 molecules in the body (at 100% saturation)
Fortunately, we can understand the whole process at thelevel of the single Hb molecule
280 x 106 Hb molecules per RBC
Hb is a tetramer (M.W. ~ 68,000), composed of 4 similar units
Each unit consists of a “heme” ring structure, which binds
& a polypeptide chain (globin) which binds CO2, H+, phosphates etc.
Fig 16-3
1 Hb = 4 globins + 4 hemes
Note: binding of O2 to Fe2+ is via an ionic bond, not an oxidation-reduction reaction
2 alphachains of141 aa’s
2 betachains of146 aa’s
All identical
A “functional” model of Hb
- - - - - - - - - - - - - - - -
Fe2+
Fe2+
Fe2+
Fe2+
-
-
-
-
- - - - - - - - - - - - - - - -
- - - - - - - - - - - - - - - -
- - - - - - - - - - - - - - - -X X X XX
X X X X X
X X X X X
X X X X X
Hemes GlobinsH+ H+ H+ H+ H+
H+ H+ H+ H+ H+
P P P P P
P P P P P
Hb exhibits the property of allosteric modulation = “binding at one site on a molecule affects binding at a second site, usually by changing the shape of the
molecule.”
CO2
CO2
CO2
CO2
O2
O2
O2
O2
A “functional” model of Hb
- - - - - - - - - - - - - - - -
Fe2+
Fe2+
Fe2+
Fe2+
- NH2
- NH2
- NH2
- NH2
-
-
-
-
- - - - - - - - - - - - - - - -
- - - - - - - - - - - - - - - -
- - - - - - - - - - - - - - - -X X X XX
X X X X X
X X X X X
X X X X X
O2
O2
O2
O2
Hemes Globins
CO2
CO2
CO2
CO2
H+ H+ H+ H+ H+
H+ H+ H+ H+ H+
P P P P P
P P P P P
H+, CO2, & phosphate are negative allosteric modulators of O2 binding
O2 is a negative allosteric modulator of H+, CO2, & phosphate binding
O2 is a positive allosteric modulator for for further O2 binding
- 1st O2 helps the 2nd, & the 2nd helps the 3rd; 4th is not helped
Hb Hb(O2)4
High PO2 at the lungs promotes the formation of
exyhemoglobin
Low PO2 at the tissues promotes the formation of
deoxyhemoglobin
4x O2
This allosteric co-operativity is the reason for the sigmoidal(S-shaped) “O2 dissociation (association?) curve” of the blood
This is simply a plot of the extent of a chemical reaction - the driving force (PO2) versus the amount of product (%Hb-
O2)
(Product =% Hb-O2)
(driving force)Fig 18-8
PaO2PvO2
0
50
100
150
200
ml O
2 p
er
1000 m
l b
lood
Venousreserve
Fig 18-8
Loading point in pumonary capilaries
Unloading point inSystemic capilaries
Situation at rest
Important “design features” of the sigmoidal curve:
1. Flat region at top provides an important safety margin for O2 loading during:
-high altitude exposure- respiratory diseases- shift in blood curve to right during exercise
2. Knee and steep part is strategically located to facilitate a greater O2 unloading during exercise with only a relatively small decrease in systemic tissue PO2
and therefore in PvO2
@ 40 torr ==> ~75% Hb-O2
@ 20 torr ==> ~35% Hb-O2
So a small decrease in PvO2 creates a large increase in O2 unloading during exercise .
PvO2 decreases because of increased consumption (increased metabolic rate) in the systemic tissues.
This is helped by 3 additional factors during exercise:
1. An increase in PvCO2 shifts the curve to the right PvCO2 increases because of increased CO2
production in the systemic tissues.
2. A decrease in pHv shifts the curve to the right
pHv decreases because of increased [H+] from lactic acid and CO2 production in the systemic tissues: CO2 + H2O
====> H2CO3 ====> H+ + HCO3-
3. An increase in blood temperature shifts the curve to the right.
Blood temperature rises due to greater heat production in the systemic tissues.
A “functional” model of Hb
- - - - - - - - - - - - - - - -
Fe2+
Fe2+
Fe2+
Fe2+
- NH2
- NH2
- NH2
- NH2
-
-
-
-
- - - - - - - - - - - - - - - -
- - - - - - - - - - - - - - - -
- - - - - - - - - - - - - - - -X X X XX
X X X X X
X X X X X
X X X X X
O2
O2
O2
O2
Hemes Globins
CO2
CO2
CO2
CO2
H+ H+ H+ H+ H+
H+ H+ H+ H+ H+
P P P P P
P P P P P
H+, CO2, & phosphate are negative allosteric modulators of O2 binding
O2 is a negative allosteric modulator of H+, CO2, & phosphate binding
PCO2 = 55 TorrpH 7.6
pH 7.4
pH 7.2 Temp = 39ºC
P50
Loading point at restUnloading point at rest
Unloading point during exercise
PCO2 = 55 TorrpH 7.6
pH 7.4
pH 7.2 Temp = 39ºC
During exercise, O2 unloading can be increased to 90% (ie
venous reserve decreased to 10%) by combined effect of
PvO2, PvCO2, pHv and temp.
Unloading pt. during exercise
Loading pt.During exer.
Loading pt. during rest.Unloading pt. during rest.
Biology 2A03Lecture 26
Respiration IV
O2 bound to Hb, does not directly Contribute to PO2 => only dissolved
O2 does.
O2 bound to Hb does not directly Contribute to the total amount of
O2 that will diffuse.
Important “design features” of the sigmoidal curve:
1. Flat region at top provides an important safety margin for O2 loading during:
-high altitude exposure- respiratory diseases- shift in blood curve to right during exercise
2. Knee and steep part is strategically located to facilitate a greater O2 unloading during exercise with
only a relatively small decrease in systemic tissue PO2, and therefore in PvO2.
@ 40 torr ==> ~75% Hb-O2
@ 20 torr ==> ~35 % Hb-O2
So a small decrease in PvO2 creates a large increase in O2 unloading during exercise.
PvO2 decreases because of increased O2 consumption (increased metabolic rate) in the systemic tissues.
This is helped by 3 additional factors during exercise:
1. An increase in PVCO2 shifts the curve to right.
PvCO2 increases because of increased CO2 production in the systemic tissues.
2. A decrease in pHv shifts the curve to the right.
pHv decreases because of increased [H+] from lactic acid & CO2 production in the systemic
tissues:
3. An increase in blood temperature shifts the curve to the right .
Blood temperature rises due to greater heat production in the systemic tissues.
Bohr Shift
A “functional” model of Hb
- - - - - - - - - - - - - - - -
Fe2+
Fe2+
Fe2+
Fe2+
- NH2
- NH2
- NH2
- NH2
-
-
-
-
- - - - - - - - - - - - - - - -
- - - - - - - - - - - - - - - -
- - - - - - - - - - - - - - - -X X X XX
X X X X X
X X X X X
X X X X X
O2
O2
O2
O2
Hemes Globins
CO2
CO2
CO2
CO2
H+ H+ H+ H+ H+
H+ H+ H+ H+ H+
P P P P P
P P P P P
H+, CO2, & phosphate are negative allosteric modulators of O2 binding
O2 is a negative allosteric modulator of H+, CO2, & phosphate binding
Increasing temp weakens the ionic bond between Iron and O2
PCO2 = 55 Torr
Temp = 39ºC
Unloading at rest Loading at rest
pH 7.4
pH 7.2
Unloading during exercise
P50, where 50% of O2 is bound to Hb
Loading point at restUnloading point at rest
Unloading point during exercise
PCO2 = 55 TorrpH 7.6
pH 7.4
pH 7.2 Temp = 39ºC
Loading point
during exercise
During exercise, O2 unloading can be increased to 90% (i.e. venous reserve decreased to 10%) by combined effect of
Organic phosphate molecules are also important negative allosteric modifiers of O2 binding, but play
little role during exerciseMammals - 2,3 diphosphoglycerate (2,3 DPG)
Birds – inositol pentaphosphate (IP’s)
Fish & amphibians – ATP and GTP
Increase in RBC [phosphate] shifts curve to the right in most mammals during anemia, high altitude and respiratory diseases.
This helps improve O2 unloading to the systemic tissues
However some mammalian species which are native to high altitude have very low levels of RBC [2,3-DPG],
therefore a left shifted curve => an adaptation to improve O2 loading?
The situation is parallel in fish during chronic hypoxia(decrease in oxygen)
Mammalian fetus has a different Hb ==> Hb-f in which 2 gamma chains (different a.a. sequence) replace 2 beta chains
Hb-f is very insensitive to 2,3 DPG, so fetal curve is to the left of the maternal curve => facilitates O2
transfer across the placenta.
Muscle Mb curve is to left of blood Hb curve ===> facilitates O2 transfer from blood to the muscles
% Hb-O2
PO2 (torr)
Mucles (Mb)
Blood (Hb)
Biology 2A03Lecture 27
Respiration V
CO2 Transport in Blood
10 % - physically dissolved in plasma and RBC cytoplasm
30% - chemically combined with hemoglobin (Hb) as carbamino-CO2
There is a lot more CO2 than O2 in the blood
60% - as the HCO3- ion, mainly dissolved in the plasma
CO2 + H2O <====> H2CO3 <====> H+ + HCO3-
slow fast
carbonic anhydrase
XBuffered
by HbMoves into plasma in
exchange for Cl-
Carbonic anhydrase is the 2nd most abundant protein in RBC’s after Hb.
90% depends on presence of Hb & RBC’s
Both of these reactions tend to shift curve to the right, thereby helping to
unload O2.
“Band 3” Cl-/HCO3- exchange
= chloride shift
Fig 18-11
Most bicarbonate transported in
plasma
Driving pressureCells ==> capillary
Both of these reactions tend to shift curve to the
left, thereby helping to load O2 into the cells.
Fig 18-11
Driving pressure for CO2Driving pressure for CO2
Driving pressure for CO2 blood => alveoli
Even at rest, small H+ & CO2 Bohr effects and temp. effects shift the O2 dissociation curve slightly to the
right in the systemic capillaries, .
So the Bohr Effects (and temperature effects) are not just restricted to exercise.
The reverse happens at pulmonary capillaries, the O2 dissociation curve is shifted slightly to the left,
thereby helping O2 .
The Haldane Effect - the Mirror Image of the Bohr Effect (again a negative allosteric
effect)The addition of O2 to the Hb
helps to unload CO2 at the pulmonary capillaries
The removal of O2 from the Hb helps to load at the systemic capillaries
While these effects are small at rest, they become
much more important during exercise
Central Regulation of Ventilation
Fig 18-15
Apneustic center
Pneumotaxic center
Respiratory control center
Rhythmicity center
I neurons E neurons
Spinal cord
Ventilatory muscles for inhalation(Diaphragm and intercostals)
x x
1) Regulation of inhilation/exhalation rhythm2) Regulation of rate and depth
Autorhythmicity and inhibit each other
Fires duringInhilation
Fires during exhalation
Always ON(not rhythmic)
Cyclically active(has a pacemaker)
Stimulates inhilation Terminates inhilation
Apneustic and pneumotaxic centers: in pons sets pattern and depth of breathing
I and E neurons of the rhythmicity center: in medulla set the rate of breathing
Central Regulation of Ventilation
Activity of the whole “respiratory control center” is affected by:
-Movement and position receptors in limbs (joint-tendon receptors)
-Stretch receptors in windpipe
-Plasma hormones (e.g. epinephrine increases ventilation)-Plasma K+, lactate
Peripheral chemoreceptors: monitor PaO2, pH, PaCO2
Central chemoreceptors: monitor PaCO2 (arterial)
Central Chemoreceptors
Figure 18.20
More sensitive and accurate than peripheral
chemoreceptorsMonitors PaCO2 through
changes in cerebral spinal fluid (CSF) and a resulting change in
pHCO2 can cross blood-brain barrier while H+ cannot easily
cross this barrier
Lots of carbonic anhydrase in the CSF
Central Chemoreceptors
Central chemoreceptors are the most important controls of breathing
Located in the medulla near the rhythmicity centre and monitors PCO2 only
Actually monitors the pH of the ECF (CSF) and reflects the PCO2 of the CSF
Even slight increase from a setpoint of PaCO2= 40.5 Torr will cause CSF pH to decrease and
stimulate ventilation (and vice versa)
Every breath is triggered by a slight increase in PaCO2
Peripheral (“Arterial”) Chemoreceptors
- connected to “respiratorycontrol centre” in pons & medulla
via glosso-pharyngeal nerves (IX)(afferent branches)
pons
medulla
via vagus nerves (X)(afferent branches)
Note: do not confuse with arterial baroreceptors, which
are a separate system.Fig 18-18
CarotidChemareceptors
Peripheral (“Arterial”) Chemoreceptors- monitor PaO2 (setpoint ~ 100 torr) ===> stimulate
ventilation in response to decreases PaCO2 (not very sensitive to small changes) though small decreases
sensitize the responsiveness to increased PaCO2- monitor pHa (set point ~ 7.4) ===> stimulate
ventilation in response to decreased pHa (increased [H+]), & vice versa.- monitor PaCO2 ( set point ~ ) ===> stimulate
ventilation in response to increased , & vice versa (direct & indirect responses?), backing up central
receptors- mainly a fine-tuning, back-up and safety system which becomes more important during special circumstances:
- new-born infants
- Drug and alcohol narcosis
- High altitude – low PaO2 - Severe exercise – decreased pHa due to lactic acid
Biology 2A03Lecture 28
Respiration VI
Peripheral (“Arterial”) Chemoreceptors
- connected to “respiratorycontrol centre” in pons & medulla
via glosso-pharyngeal nerves (IX)(afferent branches)
pons
medulla
via vagus nerves (X)(afferent branches)
Note: do not confuse with arterial baroreceptors, which
are a separate system.Fig 18-18
Carotid chemoreceptors
Aorticchemoreceptors
Peripheral (“Arterial”) Chemoreceptors- monitor PaO2 (setpoint ~ 100 torr) ===> stimulate ventilation in response to decreases in PaO2 (not very
sensitive to small changes) though small decreases sensitize the responsiveness to increased PaCO2
- monitor pHa (set point ~ 7.40) ===> stimulate ventilation in response to decreased pHa (increased
[H+]), & vice versa.- monitor PaCO2 (set point ~40.5 torr) ===> stimulate ventilation in response to increased PaCO2, & vice versa
(direct & indirect responses?), backing up central receptors- mainly a fine-tuning, back-up and safety system which
becomes more important during special circumstances: - New born infants
- Drug or alcohol narcosis
- High altitude (low PaO2)
- Severe exercise (decrease pHa due to lactic acid)
mediated entirely via peripheral chemoreceptors
mediated almost entirely via
Peripheral chemoreceptors
(H+ does not easily cross blood brain barrier)
Fig 18-19
% sat drops
Hyperventilation decreased PCO2 and therefore H+
pH change not due to PCO2 (eg lactate during exercise)
Fig 18-19
Mediated via the central chemoreceptors
Respiratory and circulatory systems create a balanced pH (acid/base content) of the body
Acid-Base Balance- the control of ECF and ICF pH
Chapter 18, pp 568-571 & Chapter 20, pp. 632- 641
We focus on ECF pH ==> normal arterial blood plasma pHa ~7.4
ICF (cytoplasmic pH ~7.0) depends critically on ECF pH 7.4
7.00 <======7.20 <==7.40 ==> 7.60 ======> 7.80
There are 2 major buffer systems in the blood that minimizechanges in free [H+] and [OH-]
1. Protein system (e.g. Hb, plasma proteins): H+ + Protein (neg) => H-Protein
OH- + H-Protein => H2O + Protein
2. CO2/HCO3- system:
H+ + HCO3- CO2 + H2OOH- + CO2 HCO3-
Depression of the nervous system
(coma)Normal pH
Over excitation of the nervous system – tetany of muscles
Minimizes but doesn’t reverse pH changes
The protein and CO2 buffer systems are in equilibrium with each other, & with all other less important buffer systems (e.g. phosphate, ammonia) - by the isohydric
principle.Only the CO2/HCO3- buffer system is subject to active
physiological regulation – the others follow passively .
The major principles of acid-base regulation can be understood by following the CO2/HCO3
- system.
If CO2 is excreted as fast as it is produced in metabolism, there is no net acid-base effect (i.e.
equilibrium):
CO2 + H2O <====> H2CO3 <====> H+ + HCO3
-
carbonicanhydrase
Reaction does not go to equilibrium because HCO3- exported to the plasma by Chloride Shift
CO2 + H2O <====> H2CO3 <====> H+ + HCO3-
carbonicanhydrase
Respiratory Acidosis - If CO2 production exceeds excretion by ventilation==> net H+ and HCO3-
buildupRespiratory Alkalosis - If CO2 excretion by ventilation exceeds production ==> net H+ and HCO3- loss
Metabolic Acidosis - If an acid (H+) other than CO2 is added to the blood (e.g. lactic acid) , reaction is driven
to the left, and a HCO3- is lost-If a HCO3
- is lost directly (e.g. diarrhea), reaction is pulled to the right, and an H+ ion is added to the
blood.Metabolic Alkalosis - If a base (OH-, HCO3- ) is added to
the blood, it forms or adds HCO3-, reaction is driven to
the left, and an H+ oin is lost - If an H+ is lost directly (e.g. vomiting) , reaction is
pulled to the right, and a HCO3- is added to the blood.
For these “Metabolic” disturbances:
net H+ loss = net HCO3- gain
net H+ gain = net HCO3- loss
For “Respiratory” disturbances, H+ and HCO3- are net gained
or net lost in equal amounts as CO2 is gained or lost:
CO2 + H2O <====> H2CO3 <====> H+ + HCO3-
carbonicanhydrase
Respiratory disturbances -due to a disturbance of dissolved plasma [CO2] which is
regulated by breathing - fast (sec - min) :
Dissolved [CO2] = PaCO2 x Sol. Coefficient (aCO2)
Metabolic disturbances - due to a disturbance of plasma [HCO3-] which is regulated by metabolism
& kidney function - slow (hours - days)
Constant
(H. Smith (1954) - “a most useful monument to human laziness”)
pH = pK + log [anion of acid]/[acid] = 4.0 + log[HCO3-]/[H2CO3]
However: [H2CO3] <===> Dissolved [CO2] = PaCO2 x aCO2
c.a.
The Henderson-Hasselbalch Equation
pHa = pK’ + log [HCO3-] = ~ 6.1 + log [HCO3
-] Diss. [CO2] PaCO2 x aCO2
constant constant
Regulated by breathing ~ fast
constant
Regulated by metabolism & kidney ~slow
pHa = ~ 6.1 + log [HCO3-]
PaCO2 x aCO2
The log stuff is approx 20 normally)pHa = 7.4
pHa is regulated at 7.4 by keeping [HCO3-] at 20
PaCO2 x aCO2*Respiratory acidosis - PaCO2 is too high (therefore pHa
too low) due to hypo-ventilation. -If it’s a chronic effect, kidney slowly compensates by
accumulation of HCO3- (excreting H+).
Respiratory alkalosis - PaCO2 is too low (therefore pHa too high) due to hyper-ventilation.
-If it’s a chronic effect, kidney slowly compensates by excreting HCO3- (accumulation
of H+).
24 mmoles/L40.5 torr * 0.03 mmoles/L
pHa is regulated at 7.4 by keeping [HCO3-] at 20
PaCO2 x aCO2*
Metabolic acidosis - [HCO3-] is too low (therefore pHa
too low) - e.g due to addition of lactic acid to blood.
Metabolic alkalosis - [HCO3-]is too high (therefore pHa too
low) - e.g due to metabolism of some foods.
-Ventilation increases quickly to compensate, thereby lowering PaCO2.
-Ventilation decreases quickly to compensate, thereby raising PaCO2.
Quiz 3 March 26th in lecture time slot.
35 multiple choice questions
75% on new material (including Labs)25% on material from Quiz 1 and 2
Same room assignments
Bring calculator and i.d.
Course evaluation at end of lecture this Friday
Biology 2A03Lecture 29
Respiration VII
Hormones I
(H. Smith (1954) - “a most useful monument to human laziness”)
pH = pK + log [anion of an acid] = 4.0 + log [HCO3-]
[acid] [H2CO3]
However: [H2CO3] <===> Dissolved [CO2] = PaCO2 x aCO2
c.a.
======>The Henderson-Hasselbalch Equation
pHa = pK’ + log [HCO3-] = ~ 6.1 + log [HCO3
-] Diss. [CO2] PaCO2 x aCO2
~constantconstant
~constant
regulated by metabolism & kidney -slow
regulated by breathing -fast
pHa = ~ 6.1 + log [HCO3-]
PaCO2 x aCO2
pHa = ~6.1 + log 20 = 7.4
pHa is regulated at 7.4 by keeping [HCO3-] at 20
PaCO2 x aCO2*Respiratory acidosis - PaCO2 is too high (therefore pHa
too low) due to hypo-ventilation. -If it’s a chronic effect, kidney slowly compensates by
accumulating HCO3- (excreting H+)
Respiratory alkalosis - PaCO2 is too low (therefore pHa too high) due to hyper-ventilation
-If it’s a chronic effect, kidney slowly compensates by excreting HCO3
- (accumulating H+)
24 mmol/L
40.5 Torr x 0.03 mmol/Torr
pHa is regulated at 7.4 by keeping [HCO3-] at 20
PaCO2 x aCO2*
Metabolic acidosis - [HCO3-] is too low (therefore pHa
too low) - e.g due to addition of lactic acid to blood.
Metabolic alkalosis - [HCO3-]is too high (therefore pHa too
high) - e.g due to metabolism of some foods.
-Ventilation increases quickly to compensate, thereby lowering PaCO2.
-Ventilation decreases quickly to compensate, thereby raising PaCO2.
Fick Principle for O2 consumption:Tissue VO2 = Q x (CaO2 – CvO2)
=5L/min (200 ml O2/L – 150 ml O2) = 250 ml/min
Alveolar O2 transport:VAO2 = (VT – VD) x f
=(500 ml/breath – 150 ml/breath)
x 12 breaths /min= 4200 ml/min x 0.21 = 882 ml/min O2.Blood O2 Transport:
TO2 = Q x CaO2
Where: CaO2 = O2dissolved + O2.Hb
=3ml O2 L-1 +(1.34 ml O2 g-1 Hb)(150g Hb L-1)= 200 ml O2 / L
= 5 L/min x 200 ml 02/L= 1000 ml/min O2
During heavy exercise= 22 L/min (200 – 80 ml
O2)= 2800 ml/min
The ob gene encodes the hormone leptin
The ob / ob obesity mouse
Endocrinology
The Endocrine System (Chapter 5 (140-143, 157-158) – Ch 6)
- the other long-distance communication system in the body.
- slow, long-lasting messages carried in the blood-stream, with long-lasting effects.
- not completely separate from the .
(1) are often under nervous control.
- endocrine glands ==> secrete products .
(exocrine glands ==> secrete products to outside or via a duct leading to outside)
(2) Many hormones are released as .
(3) Many substances which act as hormones in the general circulation serve .
(4) The hypothalamus-pituitary complex is the .
e.g. GH, ADH
Adipose tissuee.g. leptin
e.g. TH
e.g. Epicortisol
ANP
Renin, EPO
estrogen
testosterone
e.g. insulinsomatostatin
3 Classes of Hormones1. Amines (derived from a.a.
- Adrenomedullary hormones (catecholamines):
Dopamine - n/t & hypothalamic hormone which
Norepinephrine & epinephrine -
- Serotonin (5-hydroxytryptamine) -n/t & hormone derived from
tryptophan - involved in sleep, surpressing stress responses, &
moods. - Thyroid hormones (T4 = thyroxine, T3= triodo-thyronine) derived from tyrosine - regulate
metabolic rate, growth, brain development.
Other amines:
1
2
3
4
synth
Bio 2A03Lecture 30
Hormones I
The ob gene encodes the hormone leptin
The ob / ob obesity mouse
The Endocrine System (Chapter 5 (140-143, 157-158) – Ch 6)
- the other long-distance communication system in the body.
- slow, long-lasting messages carried in the blood-stream, with long-lasting effects.
- not completely separate from the nervous system.
(1) Endocrine glands are often under nervous control.
- endocrine glands ==> secrete products directly into ECF.
(exocrine glands ==> secrete products to outside or via a duct leading to outside)
(2) Many hormones are released as n/t’s from neurons.
(3) Many substances which act as hormones in the general circulation serve as n/t’s in the brain.
(4) The hypothalamus-pituitary complex is the neuro-endocrine interface.
(see Table 5-6 for comparison with NS)
e.g. GH, ADH
Adipose tissuee.g. leptin
e.g. TH
e.g. Epicortisol
ANP
Renin, EPO
estrogen
testosterone
e.g. insulinsomatostatin
1. Amines (derived from a.a. tyrosine, tryptophan):- Adrenomedullary hormones
(catecholamines): Dopamine - n/t & hypothalamic
hormone which inhibits prolactin secretion
Norepinephrine & epinephrine - n/t’s & adrenomedullary
hormones
- Serotonin (5-hydroxytryptamine) -n/t & hormone derived from
tryptophan - involved in sleep, surpressing stress responses, &
moods. - Thyroid hormones (T4 = thyroxine, T3= triodo-thyronine) derived from tyrosine - regulate
metabolic rate, growth, brain development.
Other amines:
1
2
3
4
synth
3 Classes of Hormones
Need to know enzymes and order
2. Protein & Polypeptide Hormones- the major class of hormones.
- synthesized by proteolytic cleavage of pre-prohormones on E.R.,
& resulting prohormones are then often further cleaved to hormones during packaging into vesicles by Golgi apparaatus.- hormones (& pro-hormones, & “pro-fragments”) are
released by Ca2+-initiated exocytosis.
Similar to Fig 5-4
3. Steroid Hormones -derived from cholesterol
- the second major class of hormones.
- produced by gonads (sex hormones), placenta (female sex hormones), and adrenal cortex (mineralocorticoids,
glucocorticoids, & sex hormones).
glucocorticoid mineralocorticoid Sex hormones
Similar to Fig 5-5
Ring structure of cholesterol preserved so all have
lipophilic nature (can’t be stored in vesicles)
Table 5-5
Functionally, the 3 hormone classes based on chemical origin break down into two groups:
A. Peptides, Proteins , Serotonin & Catecholamines
B. Steroids & Thyroid HormonesA B
*(but endocytosis may occur)
*
Metabolic breakdown & rapid ( < 1 h) slow (hours - days)excretion
Effects on Target Cells:
1. Direct - activate or inhibit some function of the cell.
2. Indirect = “permissive effects” - alter the sensitivity of the target cell to other hormones by up-regulating or
down-regulating their receptors
Controls on Hormone Secretion:
1. Changes in plasma [nutrients] or [ions] - e.g. [glucose] on insulin & glucagon; [Ca2+] on calcitonin
& parathyroid hormone
2. Another hormone (or self-inhibition) - e.g. hypothalamic releasing/ inhibiting hormones on anterior
pituitary hormones3. Neural controls - direct from CNS (hypothalamic
hormones) or via the autonomic nervous system
Direct CNS Control Via Autonomic N.S.
Portal system
Hypothalamus -Pituitary Complex:- “master endocrine gland(s)”- “neuro-endocrine interface”
Posterior Pituitary - neural tissue“neurohypophysis”
Hypothalamus - neural tissue
Axons terminate in the posterior pituitary
Release of neurohormones
PVN
Bio 2A03Lecture 31
Hormones II
Hypothalamus -Pituitary Complex:- “master endocrine gland(s)”- “neuro-endocrine interface”
PVN
Posterior Pituitary- neural tissue “neurohypophysis”
Axons terminate in the posterior pituitary
Hypothalamus- neural tissue
Release of neurohormones
Posterior Pituitary Hormones-”octapeptides” (8 a.a.’s peptides) synthesized in soma of
giant neurons of the hypothalamus.
-slowly transported down the giant axons by axonal transport & stored like neurotransmitter in synaptic vesicles
in terminal knobs on blood vessels in post. pituitary.- released by A.P’s coming down giant axons
1. Antidiuretic Hormone = ADH = Vasopressin
- released as a response to low blood volume, low blood pressure, high ECF osmotic pressure (hypothylamic
osmoreceptors).- promotes water retention at kindey and raises blood pressure by vasocontricting systemic arterioles.
- from giant neurons of supra-optic nucleus (5/6 with 1/6 from PVN.)
2. Oxytocin- from giant neurons of paraventricular nucleus
- reproductive functions – uterine contractions, milk ejection, orgasm (?)
Anterior Pituitary
Hypophysiotropic hormone
Anterior pituitary hormone
Tropic stimulates the release of another
hormone
Hypothalamus- pituitary portal system
Hypothalamic & Anterior Pituitary Hormones
At least 6 different (probably more) Hypophysiotropic
hormones = Releasing Hormones (factors) + Inhibiting Hormones (factors),
from 6 different giant neuron groups
5 different cell types release at least 6 different
anterior pituitary hormones which pass out
into general circulation
Very high local concentration (no dilution
with general circ.)
Hypophysiotropic hormones - released like NT’s by A.P.’s- All are short polypeptides (3-44 A.A.’s) except dopamine
1. Gonadotropin Releasing Hormone (GnRH) – stimulates both LH & FSH release.
2. Growth Hormone Releasing Hormone (GHRH) – stimulates GH release.
3. Somatostatin (SS) = Growth Hormones Inhibiting Hormones (GHIH)- inhibits GH release.
4. Thyrotropin Releasing Hormone (TRH) – stimulates TSH release.
5. Dopamine = Prolacting Inhibiting Hormones (PIH)- inhibits prolactin release.
6. Corticotropin Releasing Hormone (CRH) – stimulates ACTH release
Anterior Pituitary Hormones - all long polypeptides or proteins
* 1. Luteinizing Hormone (LH) – promotion of ovulation, formation of corpus luteum, & sex hormone production.
* 2. Follicle Stimulating Hormone (FSH) – promotion of ovarian follicle development, sperm production, & sex hormone
production.
*3. Growth Hormone (GH) – general actions on most tissues: promotes IGF-1 release (which promotes growth); protein
synthesis, alters carbohydrates and lipid metabolism* 4. Thyroid Stimulating Hormone (TSH) – stimulates thyroid
growth, T3 & T4 production.5. Prolactin (PL) - general reproductive functions, promotion
of breast development & milk production; suppresses ovulation during breast-feeding; ionoregulation effects (?)
6. Adrenocorticotrophic Hormone (ACTH) - promotes glucocorticoid production by the adrenal cortex chronic
stress coping responses mainly mediated by cortisol.
* All tropic hormones
Gonadotropins from same anterior pituitary cells
Fig 6-5
T3, T4
Neural Input from Higher CentersOther Hormones
+/-
e.g. stress+
-
+-
-
↑
Fig 6-6
Short loop –ve feedback
prevents the buildup of
excess anterior pituitary tropic
hormone
CRH
ACTH
CORTISOL
With long loop the target
hormone limits the secretion of
tropic hormones and therefore its
own release
Biol 2A03
Lecture 32
Muscle 1
Skeletal Muscle
- Connected to at least 2 bones
- Some exceptions: some facial muscles, larynx,
external urethral sphincter
Smooth Muscle
- No striations - Found in blood vessels,
GI tract, uterus
Cardiac Muscle
- Show characteristics of both skeletal & smooth
muscles
Comparison of skeletal, smooth and cardiac muscle
Structure of a skeletal muscle fiber (cell)
Neuromuscular junction
Mitochondria
SS – subsarcolemmal IM - intramyofibril
Multinucleated cells
Muscles made up of bundles (fascicles) of muscle fibers
Myofibrils
sarcomere
Each fiber (cell) controlled by only
1 motor neuron
The Sarcomere
-Sarcomeres are bordered by Z line which anchor thin filaments (actin) (blue)
-Thick filaments are joined at the M line (myosin) (red)
A band. Entire myosin bundle + overlapping regions of actin.
I band. Regions of actin filaments which do not overlap myosin. Bisected by Z line.
H zone. Area of sarcomere between opposing ends of actin filaments.
Classic features of sarcomeres
Thick Filament (Myosin)
100’s of myosins per thick filament arrange in a staggered fashion along the TF (think filament).
Each myosin is a dimer of 2 intertwined subunits
crossbridge
Tropomyosin partly covers the myosin
cross-bridge binding site
Ca2+ binding to troponin causes change in shape of molecule.
Troponin bound to tropomyosin. Therefore conformational change
to troponin drags tropomyosin away from cross-bridge binding
site.
Thin Filaments
Backbone composed of actin. G-actin (for globular protein) bind together to form F-actin (fibrous protein).
Sliding-Filament Theory of muscle contraction
Actin and myosin do not shorten but rather the thick and thin
filaments slide past each other.
The crossbridge cycle
Ca2+ essential for crossbridge
attachment
Excitation-contraction coupling
Voltage-sensitive receptor
(affected by depolarizatio
n of the membrane)
Coupled to SR Ca2+ channels
Muscles have excitable
membranes
1. Action potential targets charged amino acid
residues in DHP.
2. DHP conformation change which, via foot
proteins, opens ryanodine channel.
3. Ca2+ released from sarcoplasmic reticulum
into cytosol.
DHP = dihydropyridinereceptors.
Recruitment of motor units
1. Motor units
Motor unit: motor neuron and all the fibers
that it innervates5 fibers
7 fibers2. A muscle can have
hundreds of motor units.
The size principle units are recruited for small muscle forces. units are used for larger forces
Larger than average that are harder to . They also have
larger
Biology 2A03
Lecture 33
Muscle II
The Last One!
Recruitment of motor units
1. Motor units differ in size
Motor unit: motor neuron and all the fibers it
innervates5 fibers
7 fibers2. A muscle can have
hundreds of motor units. Muscle tension can be
varied greatly
The size principle Small motor units are recruited for small muscle forces. Larger motor units are used for larger forces
Larger than average cell bodies that are harder to depolarize. They also have
larger axon diameters
Greater the AP from the brainthe larger the motor units that
are recruited, and the larger thetension/force produced.
-When stimulated these different muscles take different times to reach peak tension
-They each contain different populations of muscle fibers
Extraocular myosinPrimarily Type II myosins
Primarily Type I myosin
- Contraction properties depend on proportions of fast and slow twitch fibers (proportions of fast and slow
myosins)
Some muscles generate moretension/force than others…this
graph is mis-leading.
Skeletal muscle fibre classificationMaximal shortening velocity – fast or slow fibres
In fast fibres cross-bridge shortening is approximately 4x faster than in slow fibres
ATP supply: oxidative or glycolyticOxidative fibres. -Mitochondria rich.
-ATP derived from oxidative phosphorylation. -Highly vascularised.
-Contain large amounts of oxygen transporting myoglobin. --Often called red muscle.
Glycolytic fibres. -Few mitochondria.
-ATP derived from glycolysis. -Rich in glycolytic enzymes.
-Poorly vascularised. -Small amounts of myoglobin. = White muscle.
Type I Type IIa Type IIbAlso named for Myosin
isoform (I, IIa and IIb)
Muscles with low mitochondria are well suited for short bursts of energy use,Eg. In sprinters. Muscles with high mito levels are well suited for long-term endurance,Eg. In marathon runners. The two cannot be converted…but high mito can be trainedTo work over shorter distances…low mito cannot be trained for endurance as easily.
Lack the striations of skeletal muscle. Controlled by autonomic nerves = involuntary control.
Mononucleate (skeletal = multinucleate) Smooth Muscle can divide throughout life of an
individual (skeletal = unable to divide once differentiated).
Smooth muscle division can be stimulated by paracrine agents.
Smooth Muscle
-Calmodulin the Ca2+ binding regulatory protein NOT troponin-tropomyosin
No regular alignment of myosin and actin as occurs in skeletal muscle
Dense bodies. Functionally equivalent to Z-lines in
skeletal muscle
-Ca-calmodulin complex binds to a myosin kinase which phosphorylates myosin. Only phosphorylated myosin can bind with actin. A Phosphatase will dephosphorylate for relaxation.
PSNS and / or PNS
Inputs influencing smooth muscle (SM) contraction1. Spontaneous AP in plasma membrane of SM cell (e.g.
pacemaker cells in intestinal tract)2. Autonomic NS neurotransmitter release (SNS + PSNS)
3. Hormones (e.g. epinephrine)4. Local chemical changes (e.g. active and reactive
hyperemia)5. Stretch (myogenic response)
Smooth muscle fibres do not have motor end-plate (unlike skeletal
muscle fibres).
Neurotransmitters in smooth muscle may have a stimulatory or inhibitory effect.Neurotransmitter is released, and diffuses over to the
muscle fibres to create the appropriate response. No direction junction.
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