Membrane Function
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Transcript of Membrane Function
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Membrane FunctionMembrane Function
Signal Transduction
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I. Introduction to I. Introduction to Receptors & Signal Receptors & Signal
TransductionTransduction
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The PlayersThe Players
Signaling molecules Receptors G-proteins Second messenger systems Effector proteins
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Signaling MoleculesSignaling Molecules
Neurotransmitters Hormones Growth factors Drugs Other nomenclature
Ligand Agonist / Antagonist
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ReceptorsReceptors
Receptors are proteins associated with cell membranes
Receptors “recognize” signaling molecules by binding to them.
Binding of receptors by signaling molecules ---> Cell behavior change
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Figure 1: Overview of Figure 1: Overview of SignalingSignaling
TyrosineKinase
mRNASynthesis
Protein Synthesis
SecondMessangers
Protein Kinases
IonChannels
Hormones:SteroidsThyroid
GrowthFactors
TransmittersTransmitters
Hormones
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Neurotansmitters: Neurotansmitters: Biogenic Amines.Biogenic Amines.
Catecholamines Epinephrine Norepinephrine Dopamine
Esters: Acetylcholine Indolamines
Histamine 5-HT
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Neurotransmitters: Neurotransmitters: PeptidesPeptides
Substance P Neuropeptide Y (NPY) Enkephalins Somatostatin VIP
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Neurotransmitters: Amino Neurotransmitters: Amino AcidsAcids
Excitatory Glutamate Aspartate
Inhibitory -aminobutyric acid (GABA) Glycine
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Neurotranmitters: OtherNeurotranmitters: Other
Nitric Oxide Arachadonic acid Carbon Monoxide PAF Zinc
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The G-ProteinsThe G-Proteins
Involved in most signaling processes
Link receptor proteins to effector proteins.
Trimeric proteins composed of , , and -subunits.
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Figure 2: G-Protein CyclingFigure 2: G-Protein Cycling
Adenylate CyclasePhospholipase C
Ion ChannelsPhospholipase A2
Phosphodiesterase
A
A
A
A
R
R
R
R
GTP(GTPase)
-Pi
GTP
GTP
GDP
GDP
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Functional G-Protein UnitsFunctional G-Protein Units
GTP-activated -subunit produce second messenger and/or opens ion channels.
-complexes Initially thought to be inert. Probably not inert Exact role currently ill-defined.
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Second messengers Second messengers produced by G-protein produced by G-protein
activation.activation. Adenylate Cyclase cAMP
Phospholipase C (PLC) Inositol triphosphate (IP3) Diacylglycerol (DAG)
Ion Channel Activity
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Families of G-proteinsFamilies of G-proteins
Unique structure of their -subunits. subunits appear to be similar
across families. Main families:
Gs
Gi
Gq
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II. cAMP Second II. cAMP Second Messenger SystemMessenger System
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Figure 3: Adenylate Figure 3: Adenylate CyclaseCyclase
AdenylateCyclaseR1 R2
As
Gs Gi
Ai
GTPGDP
GTPGDP
PDEAMP cAMP
ATP-Mg++
Reg RegC
C
C
C
Protein
Protein-PProtein Kinase A
(PKA)PKA
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Summary of Adenylate Summary of Adenylate Cyclase ActivationCyclase Activation
Receptors which associate with Gs -type G-protein Stimulates adenylate cyclase. Increases cAMP
Receptors which associate with Gi -type G-protein Inhibit adenylate cyclase. Decreases cAMP
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Summary of cAMP actionSummary of cAMP action
cAMP exerts its effect by activating protein kinase A (PKA)
PKA phosphorylates proteins Enzymes, pumps, and channels Phosphorylation can either increase
or decrease activity depending on the protein.
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Adenylate CyclaseAdenylate Cyclase
Family of membrane spanning enzymes.
Types I through IV have been well characterized. Additional types probably exist.
Types differ with respect to activity modulation by other second messenger systems
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Adenylate Cyclase Activity Adenylate Cyclase Activity and Other Messenger and Other Messenger
SystemsSystems Kinases (PKA, PKC, other) can phosphorylate adenylate cyclase in some cells.
Binding of adenylate cyclase by: -subunits of other G-proteins Ca++/calmodulin complexes
Allows other second messenger systems to interact with cAMP system
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III. The Phospholipase C III. The Phospholipase C Second Messenger Second Messenger
System:System:IPIP33 and DAG and DAG
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Figure 4: Phospholipase C Figure 4: Phospholipase C SystemSystem
R
Ca++
PKC
Ca++Endoplasmic Reticulum
Gq
PLC
ProteinProtein-P
A
DAG
IP3
PIP2
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Summary of the Summary of the Phospholipase C Phospholipase C
MessengersMessengers Agonist binds receptor Occupied Receptor ---> activation of
PLC (Gq -mediated) PLC Produces second messengers:
IP3 and DAG PLC activation associated with
Ca++-channel activation
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Action of IPAction of IP33
IP3 binds to IP3-receptors on the endoplasmic reticulum
Releases intracellular Ca++ stores.
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Action of DAGAction of DAG
Remains membrane associated. Activates Protein kinase C (PKC)
which translocates from the cytosol to the membrane
Activated PKC phosphorylates other proteins and alters their function state.
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PLC System and CalciumPLC System and Calcium
PLC causes the IP3-mediated Calcium
PLC also causes the influx of Ca++. Ca++ binds one of a family of Ca++
binding proteins (calmodulin). Ca++/calmodulin complex
binds to yet other proteins and changes their functional activity.
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IV. Guanylate Cyclase: IV. Guanylate Cyclase: cGMP and Nitric Oxide As cGMP and Nitric Oxide As
Second MessengersSecond Messengers
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Figure 5: Nitric Oxide and Figure 5: Nitric Oxide and cGMPcGMP
cGMP
NO
Ca++
GTP
GMP
IntracellularCa++ Stores
Ca++
Ca++
Arginine
+Citrulline GTP
NO
PDE
Membrane BoundGuanylate Cyclase
SolubleGuanylate Cyclase
C.M.
Ion ChannelscGMP-Dependent PK
PDEase Activity
NO Synthetase
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NO is Membrane Soluble.NO is Membrane Soluble.
Diffusion to nearby cells Increase cGMP levels in nearby
cells Vascular endothelial cells and
nearby smooth muscle cells.
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V. SIGNALING BY V. SIGNALING BY ACETYLCHOLINEACETYLCHOLINE
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Acetylcholine As a Acetylcholine As a NeurotransmitterNeurotransmitter
Both the central and peripheral nervous systems.
Binds two broad classes of receptors: Nicotinic receptors Muscarinic receptors.
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Nicotinic Receptor Nicotinic Receptor FeaturesFeatures
Composed of 5 subunits: 2 , , and .
Subunits are arranged to form a central cavity that extends across the membrane.
Nicotinic receptors are also channels ACh-binding opens gates and allows
ion fluxes across the channel
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Figure 6: Nicotinic Figure 6: Nicotinic ReceptorReceptorChannel
AgonistBinding
Site
Gate
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Subclasses of Nicotinic Subclasses of Nicotinic ReceptorsReceptors
Skeletal muscle (N1 or Nm) Unique and subunits
Autonomic ganglia (N2 or Ng).
Both N1 and N2 are gene-product families not single receptor types.
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Other Ligand-Gated Other Ligand-Gated ChannelsChannels
Structural and sequence similarity to nicotinic receptors.
Example agonists for these channels include: Serotonin (5-HT) Glutamate GABA Glycine
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Muscarinic receptorsMuscarinic receptors
Muscarinic receptors are not channels.
Operate through G-proteins to alter second messenger systems.
5 muscarinic subtypes have been cloned and sequenced (M1, M2, M3, M4, M5).
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Grouping Muscarinic Grouping Muscarinic ReceptorsReceptors
M1, M3, and M5 receptors: Activate Phospholipase C through Gq. PLC activation ---> increased IP3 -->
increased intracellular Ca++
Increased intracellular Ca++ --->Activation of Ca++-sensitive K+ & Cl- channels.
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Grouping Muscarinic Grouping Muscarinic ReceptorsReceptors
M2 and M4 receptors Gi -coupled inhibition of adenylate
cyclase Go or Gi -coupled regulation of certain
Ca++ & K+ channels.
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VI. Signaling by VI. Signaling by Epinephrine and Epinephrine and
Norepinephrine and Norepinephrine and Coupling Through Coupling Through
Adrenergic ReceptorsAdrenergic Receptors
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Three Families of Three Families of Adrenergic Receptors:Adrenergic Receptors:
-receptors: Three subtypes and .
-receptors: Three subtypes AB and C
-receptors: Three subtypes A
B and C
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..
All adrenergic receptors All adrenergic receptors appear to be coupled to appear to be coupled to
cellular processes cellular processes through G-proteinsthrough G-proteins
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Occupation of Occupation of Adrenergic ReceptorsAdrenergic Receptors
Gs-mediated stimulation of adenylate cyclase
Increased cAMP Increased PKA activity.
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Occupation of Occupation of - -Adrenergic ReceptorsAdrenergic Receptors
Mechanistic details sketchy Possibly Gq-mediated PLC
activation Increases IP3 and DAG for some
subtypes (1B)? Activates Ca++-channels for other
subtypes (1A)?
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Occupation of Occupation of - -Adrenergic ReceptorsAdrenergic Receptors
Gi -mediated inhibition of adenylate cyclase.
Decreased cAMP Decreased PKA activity.