Calcium as a Regulatory and Signalling ion
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Transcript of Calcium as a Regulatory and Signalling ion
Calcium as a Regulatory and Signaling ion
Chiranjeevi Kumar
Tutor/Demonstrator
Dept of Physiology
AIIMS Bhopal
Calcium facts
Calcium history
Plasma calcium levels
Cellular Distribution
Ca2+ channels
Ca2+ binding proteins
Role of calcium as a regulatory and signaling ion
Calcium homeostatsis
Research on Calcium
Applied aspects
Summary
Calcium facts 2% of body weight
99% in bones
1% in body fluids
Soft grey alkaline earth metal
Occurs naturally in limestone, gypsum, and fluorite
Symbol Ca & Single oxidation state +2
Atomic Number 20 & Atomic weight 40 g/mol
Group II element in Periodic table
Divalent cation
Fifth most abundant element in Earth´s crust & Essential for life.
Calcium history Latin calx or calcis meaning ”lime”
Known as early as in first century when ancient Romans prepared lime as calcium oxide
Isolated in 1808 by Englishman Sir Humphrey Davy
In 1883 Sydney Ringer demonstrated the biological significance of calcium
Frog hearts needed the presence of calcium in the bathing solution in order to continue beating
Sir Humphry Davy, 1st Baronet (17 December 1778 – 29 May 1829) was a Cornish chemist and inventor. He is best remembered today for his discoveries of several alkali and alkaline earth metals as well as contributions to the discoveries of the elemental nature of chlorine and iodine.
He also electrolyzed a mixture of lime & mercuric acid
Plasma calcium levels In humans the concentration of calcium in the blood is – 9 - 11
mg/dL. Calcium in plasma or serum exists in three forms or fractions: 1) Protein-bound calcium 2) Ionized or free calcium 3) Complexed or chelated calcium
Ionized or free calcium is the physiologically active form
Complexed or chelated calcium is bound to phosphate, bicarbonate, sulfate, citrate, and lactate
Protein-bound calcium cannot diffuse through membranes and thus is not usable by tissues
Cellular DistributionIonic cytosol Ca is maintained at about 10-7 molar.
The differential electrical charges across the cell plasma membrane creates an electrical gradient that also favors Ca entry.
Therefore, the major threat to cell viability is excessive Ca influx from the extracellular space along the electrochemical gradients.
ECF Ca is 10-3 molar, the 1000-fold chemical gradient favors Ca entry into the cell
The defense against excess Ca influx into cells includes
Ca2+ channels Ligand gated.
Calcium channels opened after ligand binding to the receptor (e.g.
glutamate/NMDA receptor;ATP receptor; nicotinic ACh receptors ; prostaglandin
receptors
Voltage gated.
Action potental depolarizes plasma membrane, which results in the opening of
“voltage”dependent calcium channels
Each channel protein has four homologous domains, each containing six
membrane spanning α-helices (the fourth one functions as the “voltage” sensor Transient.
Long-lasting.
Store operated calcium channels.
Activated by emptying of intracellular stores, exact mechanism unknown
Type Properties Location/Function Blockers
L High activation threshold;slow inactivation
Plasma membrane of many cells;main Ca++ source for contraction insmooth and cardiac muscle
Dihydropyridine;verapamil; diltiazem
N Low activation threshold;slow inactivation
Main Ca++ source for neurotransmitterrelease by nerve terminals
ω-Conotoxin(snail venom)
T Low activation threshold;fast inactivation
Widely distributed; important in cardiac pacemaker and Purkinjecells
Mibefradil; (verapamil;diltiazem)
Ca2+ binding proteins
• Troponin.
• Calmodulin.
• Calbindin.
• Calexcitin
• Prothrombin.
• Phospholiphase A2.
• Ca2+ ATPase.
• Calsequestrin.
• Synexin
Role of calcium as a regulatory and signaling ion
Formation of bones and teeth
As a cofactor for many enzymes and proteins
As component in the blood clotting cascade
In the relaxation and constriction of blood vessels
In muscle protein degradation
In secretion of hormones as insulin
In nerve impulse transmission
As a Second messenger.
In Learning and memory.
In Muscle contraction.
In fertilization
In immune response
In Gene regulation
In Cell injury
In Modulation of ion channel activity
In visual adaptation
Role of calcium as a regulatory and signaling ion
Formation of bones and teeth
Calcium is a major structural element in bones and teeth.
Bone also acts as a store of calcium for other body functions.
This complex provides the hard and rigid structure of bone which is essential to its function.
In bone calcium and phosphate combined together in the crystalline complex; hydroxyapatite [Ca10(PO4)6 (OH)2].
Bone is a dynamic tissue that is 'remodeled' throughout life due to osteoclasts and osteoblasts
Calcium as a co-factor needed for the full activity of many enzymes, such as nitric oxide synthase, protein phosphatases, and adenylate kinase, but calcium activates these enzymes in allosteric regulation in a complex with calmodulin
catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and peristalsis
Protein kinases (PKs) are the effectors of phosphorylation
is a phosphotransferase enzyme that catalyzes the interconversion of adenine nucleotides, and plays an important role in cellular energy homeostasis.
Calcium As A Cofactor For Many Enzymes
Intrinsic Pathway and Protein Complex
Role of Calcium in Blood Coagulation
Extrinsic Pathway and Protein Complex
Role of Calcium in Blood Coagulation
Role of Calcium in Blood CoagulationClotting factors (thrombin, VII, IX and X) contain a unique modified glutamate residue, called carboxyglutamate (Gla).
This amino acid is a natural high affinity binder (or chelator) of calcium ions, hence the designation of calcium as a co-factor in the blood clotting cascade.
Synthesis of these Gla residues results from post-translational modifications of the newly synthesized factors in the liver endoplasmic reticulum by a vitamin K
Calcium - Gla-factors complex allow specific interactions with acidic membrane lipids that ultimately lead to correct tertiary and quaternary protein structures recognized by other proteins in the pathway.
Role of calcium In the constriction and relaxation of blood vessels
• Contraction in VSM can be initiated by
Passive stretching of VSM can cause contraction that originates from the smooth muscle itself and is termed as a myogenic response
The mechanism of contraction involves different signal transduction pathways, all of which converge to increase intracellular calcium.
chemical stimuli such as norepinephrin, vasopressin, endothelin-1, angiotenisin 2 and thromboxane A2 can cause contraction
Electrical depolarization of the VSM cell membrane also elicits contraction, most likely by opening voltage dependent calcium channels (L-type calcium channels)
VSM relaxation occurs when there is reduced phosphorylation of MLC. 1) reduced release of calcium by the SR or reduced calcium entry into the cell, 2) inhibition of MLCK by increased intracellular concentration of cAMP, and 3) phosphatase-activated MLC dephosphorylation.
A calpain is a protein belonging to the family of calcium-dependent nonlysosomal cysteiene proteases expressed ubiquitously in mammals and many other organisms.
Although the physiological role of calpains is still poorly understood but a transient and localized influx of calcium into the cell activates a small local population of calpains close to Ca2+ channels
Calpains have been implicated in apoptotic cell death, and appear to be an essential component of necrosis.
Calpain
Role of calcium In muscle protein degradation
These calpains activates signal transduction pathway and catalyzing the controlled proteolysis of its target proteins
Role of Calcium In secretion of hormones as insulin
22
Role Of Ca In Release Of Neurotransmitter
Role Of Ca In Release Of Neurotransmitter
Calcium influx is necessary for neurotransmitter release and Post synaptic potentiation
Voltage-gated calcium channels
Sutherland Second Messenger Hypothesis
First Messenger:Neurotransmitters
(Receptor)
AGT, GnRH, GHRH,Oxytocin, TRH
Epinephrine (α1)Acetylcholine (M1, M3)
Signal Transducer
First Messenger:Hormones
Primary effector Phospholipase C
GPCR/Gq
Catalyses PIP2Secondary effector
Second messengerIP3; DAG; Ca2+PKC; CaM
Cellular Response
Calcium – A Versatile Second Messenger
Protein kinase C:
Regulatory domain & catalytic domain tethered together by a hinge region
C1 domain, present in all of the isoforms of PKC has a binding site for DAG
C2 domain acts as a Ca2+ sensor
Catalytic Region brings about phosphorylation Ser/Thr a.a. of proteins
Upon activation, translocated to the plasma membrane
Cell type EffectsSmooth muscle (vascular)
Vasoconstriction
Smooth muscle (GIT)
Contraction
Smooth muscle (bronchi)
Bronchoconstriction
Smooth muscle (ureter/ urinary bladder/ urethral sphincter)
Contraction
Platelets Aggregation
Smooth muscle cells in
Ciliary muscle Contraction
Iris constrictor Constriction
Cellular responses of Protein kinase C
Cell type Effects
Cardiomyocytes Positive ionotropic effect
Hepatocyte Glycogenolysis,Gluconeogenesis
Adipocyte Glycogenolysis,Gluconeogenesis
Proximal Convoluted tubule Stimulate H+ secretion & Na+ reabsorptionStimulate basolateral Na+-K+ ATPase →Na+ reabsorption
neurons in CNSneurons in autonomic ganglia
neuronal excitationEPSP
sweat gland cells ↑secretion
ependymal cells (choroid plexus) ↑cerebrospinal fluid secretion
parietal cells ↑ gastric acid secretion
When calmodulin binds Ca2+, it is capable of activating five different calmodulin-dependent kinases
One of the kinases is myosin light-chain kinase, which phosphorylates myosin. This brings about contraction in smooth muscle
CaMKI is concerned with synaptic function
CaMKIII is concerned with protein synthesis
Another calmodulin-activated protein is calcineurin, a phosphatase that dephosphorylates NFATC. It also plays a prominent role in activating T cells.
Calmodulin-dependent Kinases
CaMKII is concerned with neurotransmitter secretion, transcription factor regulation & glycogen metabolism
• LTP relies on calcium influx at NMDA glutamate receptors
• Calcium channels controlled by the NMDA receptor are blocked by a magnesium ion– Magnesium ion is ejected by:
1. simultaneous glutamate binding AND
2. depolarization of the post-synaptic cell (by activity at AMPA receptors on the membrane)
Role of Ca2+ in long term potentiation
Role of Ca2+ in long term potentiation
Role of Ca in Skeletal muscle contraction
Role of Ca in Skeletal muscle contraction Role of Ca in Skeletal muscle contraction
Role of Ca in Skeletal muscle contraction
Relaxation occurs when Ca2+ is reaccumulated in the sarcoplasmic reticulum by the Ca2+ ATPase of the sarcoplasmic reticulum membrane ) SERCA(
Role of Ca in Cardiac muscle contraction
Role of Ca in Smooth muscle contraction Role of Ca in smooth muscle contraction
Smooth muscle does not contain the protein troponin;instead calmodulin, caldesmon and calponin are significant proteins expressed within smooth muscle.
Caldesmon has been suggested to be involved in tethering actin, myosin and tropomyosin, and enhance the ability of smooth muscle to maintain tension.
Calponin molecules may exist in equal number as actin, and has been proposed to be a load-bearing protein.
Role Of Calcium In Fertilization
During ovulation mammalian eggs are arrested at metaphase of their second meiotic division and remain arrested until fertilized.
These ca2+ spikes can be termed as Ca2+ oscillations which switches on calmodulin-dependent protein kinase II (CamKII), which phosphorylates the egg-specific protein Emi2.
At the time of fertilisation sperm delivers phospholipase C into the egg which triggers a series of Ca2+ spikes lasting several hours
These Ca2+ spikes are necessary for all the events of fertilization, including exit from metaphase II arrest and extrusion of cortical granules that block the entry of other sperm.
Role Of Calcium In Fertilization To remain in metaphase II, arrested eggs must maintain high levels of
Maturation-Promoting Factor (MPF) activity, a heterodimer of CDK1 and cyclin B1.
Emi2 causes blocking of cyclin B1 results in degradation of MPF
CamKII also acts as the primary initiator in the extrusion of cortical granules.
Role of calcium in Immune response
TCR stimulation
[Ca++] increases
NFATc translocates to nucleus where it combines with NFATn and induces transcription of IL-2 gene
Calcineurin: target of immunesuppressive drugs FK506 and cyclosporine, which form a complex with immunophillins and
compete with Ca++/CaM for binding to calcineurin
dephosphorylates NFATc
Binds to Calmodulin and activates Calcineurin
T cell proliferation
no NFATc activation
Role of calcium in Immune response
Role Of Calcium In Gene Expression
Hogan P G et al. Genes Dev. 2003;17:2205-2232
Cold Spring Harbor Laboratory Press
Role Of Calcium In Cell Injury
Causes of Cell InjuryOxygen Deprivation (Anoxia)
Physical Agents
Chemical Agents
Infections Agents
Immunologic Reactions
Genetic Defects
Nutritional Imbalances
Injury mechanismsDecreased Atp
Mitochondrial Damage
Increased Intracellular Calcium
Increased Free Radicals
Increased Cell Membrane Permeability
Role of calcium In Modulation of ion channel activity
• Calcium-activated potassium channels are divided into BK channels, IK
channels, and SK channels based on their conductance (big, intermediate,
and small conductance).
• This family of ion channels are activated by intracellular Ca2+.
• Calcium-activated chloride channels (CaCCs) play important roles in
cellular physiology, including
– epithelial secretion of electrolytes and water,
– sensory transduction,
– regulation of neuronal and cardiac excitability, and
– regulation of vascular tone.
Calcium-activated potassium channels
SK channels are activated by an increase in the concentration of intracellular calcium
through N-type calcium channels. Their activation limits the firing frequency of action
potentials and is important for regulating afterhyperpolarization in the neurons of
the central nervous system.
BK channels are essential for the regulation of contraction of smooth muscle and are
involved with the electrical tuning of hair cells in the cochlea.
IK channel is expressed mainly in peripheral tissues such as those of
the haematopoietic system, colon, placenta, lung andpancreas. The IK channel in red
blood cells was the first Ca2+–sensitive K+ channel to be identified
• Among all, large-conductance (BK) channels is much more sensitive to Ca2+
Each BK channel alpha subunit consists of (from N- to C-terminal):
A voltage sensing domain (S1-S4).
A K+ channel pore domain (S5, selectivity filter, and S6).
A cytoplasmic C-terminal domain (CTD) consisting of a pair of RCK (Regulator of Conductance of K+) domains
Second RCK domain. contains four primary binding sites for Ca2+, called "calcium bowls"
Role of calcium In Modulation of ion channel activity
Phototransduction
•Starts with photon absorption by rhodopsin
•Transducin binds to activated rhodopsin , exchanges GTP for GDP
•Activated transducin dissociates into and subunits
•The subunit binds to, and activates, phosphodiesterase
•Intracellular cGMP concentration decreases
•Reduction in cGMP closes cGMP-gated cation channels in the plasma membrane
•Membrane potential hyperpolarizes
•Closing of cGMP-gated channel reduces intracellular calcium
•Reduced calcium counteracts the effects of light absorption
Role of Ca2+ in visual adaptation
Role of Ca2+ in visual adaptation
Calcium homeostatsis
Exercise and Calcium
• Normal bone function requires weight-bearing exercise
• Regular physical activity has been associated with many positive
health benefits including strong bones.
• Proper calcium consumption & adequate weight-bearing
physical activity early in life is important in reaching peak bone
mass.
• Weight-bearing physical activities cause muscles and bones to
work against gravity
• Lack of weight-bearing exercise decreases bone formation
• Total bed-rest causes bone loss and negative calcium balance
Research on CalciumSee in particular:
• Calvo MS et al., “overall trend in food consumption in the US is to drink
less milk and more carbonated soft drinks.” Nutrition 2000 Vol 16 (7/8).
• Calvo MS et al., “ High sodium associated with fast-food consumption
competes for renal reabsorption of calcium and PTH secretion “
• Harland BF et al., “ Caffeine induced calcium loss “. Nutrition 2000 Vol 16
(7/8)
• Intake of carbonated beverages (soda pop) has been associated with
increased excretion and loss of calcium
• Excessive intake of Na may cause renal hypercalciuria by impairing Ca
reabsorption
Applied aspects
Hypocalcemia
Hypercalcemia
Lambert – Eaton syndrome
COFFIN – LOWRY syndrome (RPS6kA3)
Timothy's syndrome (Long QT syndrome) (LTQ1 – 13)
WOLFRAM syndrome (DIDMOAD)
Toxicology
• The UL for calcium is 1200 - 1500 mg/day
• MAS (Milk alkali syndrome)
- Rare and potentially life threatening condition in individuals
consuming large quantities of calcium and alkali
- Characterized by renal impairment, alkalosis and hypercalcemia:
cause progressive depression of the nervous system
Final word
•Calcium
A “vital life element”
not to be ignored
A very exciting area
for research
Thank you for your attention
• Rolein surfactant• Role in peripheral chemoreceptors in chemical
regulation of respiration