Calcium as a Regulatory and Signalling ion
Download as PPTX, PDF25 likes14,225 views
This document discusses calcium as a regulatory and signaling ion. It covers calcium facts, history, levels in plasma and cells. It describes calcium channels and binding proteins. The key roles of calcium include: - Formation of bones and teeth through hydroxyapatite - Acting as a cofactor for many enzymes through allosteric regulation - Playing a role in blood coagulation through binding to clotting factors - Mediating the relaxation and constriction of blood vessels - Acting as a second messenger to trigger cellular responses through calcium binding proteins like calmodulin.
![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](https://image.slidesharecdn.com/chiruseminar-1-150619160945-lva1-app6891/85/Calcium-as-a-Regulatory-and-Signalling-ion-12-320.jpg)
![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](https://image.slidesharecdn.com/chiruseminar-1-150619160945-lva1-app6891/85/Calcium-as-a-Regulatory-and-Signalling-ion-42-320.jpg)
Calcium as a Regulatory and Signalling ion
- 1. Calcium as a Regulatory and Signaling ion Chiranjeevi Kumar Tutor/Demonstrator Dept of Physiology AIIMS Bhopal
- 2. 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
- 3. 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.
- 4. 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
- 5. 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
- 6. Cellular Distribution Ionic 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
- 7. 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
- 8. Type Properties Location/Function Blockers L High activation threshold; slow inactivation Plasma membrane of many cells; main Ca++ source for contraction in smooth and cardiac muscle Dihydropyridine; verapamil; diltiazem N Low activation threshold; slow inactivation Main Ca++ source for neurotransmitter release by nerve terminals ω-Conotoxin (snail venom) T Low activation threshold; fast inactivation Widely distributed; important in cardiac pacemaker and Purkinje cells Mibefradil; (verapamil; diltiazem)
- 9. Ca2+ binding proteins • Troponin. • Calmodulin. • Calbindin. • Calexcitin • Prothrombin. • Phospholiphase A2 . • Ca2+ ATPase. • Calsequestrin. • Synexin
- 10. 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.
- 11. 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
- 12. 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
- 13. 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
- 14. Intrinsic Pathway and Protein Complex Role of Calcium in Blood Coagulation
- 15. Extrinsic Pathway and Protein Complex Role of Calcium in Blood Coagulation
- 16. Role of Calcium in Blood Coagulation Clotting 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.
- 17. Role of calcium In the constriction and relaxation of blood vessels
- 18. • 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.
- 20. 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
- 21. Role of Calcium In secretion of hormones as insulin
- 22. 22 Role Of Ca In Release Of Neurotransmitter
- 23. Role Of Ca In Release Of Neurotransmitter
- 24. Calcium influx is necessary for neurotransmitter release and Post synaptic potentiation Voltage-gated calcium channels
- 25. Sutherland Second Messenger Hypothesis
- 26. 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 PIP2 Secondary effector Second messenger IP3; DAG; Ca2+PKC; CaM Cellular Response Calcium – A Versatile Second Messenger
- 29. 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
- 30. Cell type Effects Smooth 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
- 31. Cell type Effects Cardiomyocytes Positive ionotropic effect Hepatocyte Glycogenolysis, Gluconeogenesis Adipocyte Glycogenolysis, Gluconeogenesis Proximal Convoluted tubule Stimulate H+ secretion & Na+ reabsorption Stimulate basolateral Na+-K+ ATPase →Na+ reabsorption neurons in CNS neurons in autonomic ganglia neuronal excitation EPSP sweat gland cells ↑secretion ependymal cells (choroid plexus) ↑cerebrospinal fluid secretion parietal cells ↑ gastric acid secretion
- 32. 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
- 33. • 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
- 34. Role of Ca2+ in long term potentiation
- 35. Role of Ca in Skeletal muscle contraction
- 36. Role of Ca in Skeletal muscle contractionRole of Ca in Skeletal muscle contraction
- 37. Role of Ca in Skeletal muscle contraction Relaxation occurs when Ca 2+ is reaccumulated in the sarcoplasmic reticulum by the Ca 2+ ATPase of the sarcoplasmic reticulum membrane ( SERCA )
- 38. Role of Ca in Cardiac muscle contraction
- 39. Role of Ca in Smooth muscle contractionRole of Ca in smooth muscle contraction Smooth muscle does not contain the protein troponin;instead calmodulin, cal desmon 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.
- 40. 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.
- 41. 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.
- 42. 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
- 43. Role of calcium in Immune response
- 44. Role Of Calcium In Gene Expression Hogan P G et al. Genes Dev. 2003;17:2205-2232 Cold Spring Harbor Laboratory Press
- 45. Role Of Calcium In Cell Injury Causes of Cell Injury Oxygen Deprivation (Anoxia) Physical Agents Chemical Agents Infections Agents Immunologic Reactions Genetic Defects Nutritional Imbalances Injury mechanisms Decreased Atp Mitochondrial Damage Increased Intracellular Calcium Increased Free Radicals Increased Cell Membrane Permeability
- 46. 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.
- 47. 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
- 48. • 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
- 49. 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
- 50. Role of Ca2+ in visual adaptation
- 52. 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
- 53. Research on Calcium See 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
- 54. Applied aspects Hypocalcemia Hypercalcemia Lambert – Eaton syndrome COFFIN – LOWRY syndrome (RPS6kA3) Timothy's syndrome (Long QT syndrome) (LTQ1 – 13) WOLFRAM syndrome (DIDMOAD)
- 55. 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
- 56. Final word •Calcium A “vital life element” not to be ignored A very exciting area for research
- 57. Thank you for your attention
- 58. • Rolein surfactant • Role in peripheral chemoreceptors in chemical regulation of respiration