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Calcium channels –physiology and Therapeutics uses..
Calcium channels play a key role in many cellular functions by regulating intracellular calcium levels. There are several types of calcium channels that influence calcium influx and release from intracellular stores. Voltage-dependent calcium channels include L-type, N-type, P/Q-type, R-type, and T-type channels that are involved in processes like muscle contraction, neurotransmitter release, and pacemaking. Dysfunctions in calcium channels can lead to channelopathies like hypokalemic periodic paralysis or malignant hyperthermia. Calcium channels are also important therapeutic targets, with calcium channel blockers and other drugs influencing channels to treat conditions like hypertension, angina, epilepsy, and migraines.
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Calcium channels –physiology and Therapeutics uses..
- 1. Calcium channels physiology andTherapeutics uses.. Dr . Kapil Dev Doddamani.
- 2. • Function. • Typesof Calcium channels. • Channelopathies. • Therapeutics Uses of Calcium .
- 3. Function • Signal transductionpathways, second messenger • Neurotransmitter release from neurons • Contraction of all muscle cell types • Many enzymes require calcium ions as a cofactor (blood-clotting cascade) • Extracellular calcium is also important for maintaining the potential difference across excitable cell membranes, as well as proper bone formation. •
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- 5. Ventricular AP Function •Phase 4: resting membrane potential near the K+ equilibrium potential. • Phase 0: depolarizing impulse activates fast Na+ channels and inactivates K+ channels. • Phase 1: Transient opening of K+ channels and Na+ channels begin to close. • Phase 2: Ca2+ channels are open, key difference between nerve AP. • Phase 3: repolarization, Ca2+ inactivate and K+ channels open. • Refractory period: Na+ channels are inactive until membrane is repolarized.
- 6. FUNCTION The synthesis andrelease of insulin is modulated by: 1. Glucose (most important), AAs, FAs and ketone bodies stimulate release. 2. Glucagon and somatostation inhibit relases 3. α-Adrenergic stimulation inhibits release (most important). 4. β-Adrenergic stimulation promotes release. 5. Elevated intracellular Ca2+ promotes release. Example of how an endocrine cell (pancreatic β-cell) depolarizes its membrane with Ca2+ to release insulin.
- 7. Classes of Ca+2 channels –Voltage- Sensitive (VDCCs) – Receptor- Operated (Ligand- Gated ion channels) – Leakey channels
- 9. VDCCs • The possibleexistence of VDCCs was first reported by Hagiwara in 1975 using egg cell membrane of a starfish. • They were initially divided into 2 classes HVA & LVA ca+2 channels. • HVA ca+2 channels are further divided into L,N,P/Q & R-types channels, • LVA ca+2 channels consists of only T-type channels. • R-type is occasionally classified as ( IV A ) channels.
- 10. Structure & Function L-TYPECa+2 CHANNEL • It is composed of 5 different polypeptide subunits, different mol masses ι. α1(175KD) , which forms the ion channel & contains ca+2 antagonist binding sites. ιι. α2(143KD), which is associated with α1 & does not contain any high-affinity binding site. ιιι.β(54KD), ιϖ.γ(30KD), ϖ. δ(27KD).
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- 12. N-TYPE Ca+2 CHANNEL • Itis purified from the rat brain. • It is composed of 4 subunits: ∀ α1 , α2 , γ , & β. • role -- neurotransmitter release.
- 13. P/Q-TYPE Ca+2 CHANNEL • Itis composed of α1, α2, δ & β subunits. • Play similar role - N-type calcium channel (NT release at e presynaptic terminal & neuronal integration in many neuronal types. • They are also found in Purkinje fibers in the electrical conduction system of the heart. • P channels were discovered in cerebellar Purkinje cells by Llinas and Sugimo
- 14. T-TYPE Ca+2 CHANNEL • T-typeVDCCs are activated at negative membrane potentials close to the resting potential. • the T-type channel is thought to be responsible for neuronal oscillatory activity, which is proposed to be involved in process such as sleep / wakefulness regulation & motor coordination. • In addition ,T-type ca+2 channels are involved in pacemaker activity.
- 15. CHANNEL GENE Isoform Genename Chromosomal localization Tissue distribution Biophysical properties HVA α1A α1B α1C α1D α1F α1S CACNA1A CACNA1B CACNA1C CACNA1D CACNA1F CACNA1S 19p13.1-2 9q34 12p13.3 3p14.3 Xp11.23 1q31-q32 Brain,neuronal cells,heart Brain,neuronal cells Ubiquitous Brain,neuronal,ce lls,endocrine cells Skeletal muscle P / Q –type N-type L-type L-type L-type L-type IVA α1E CACNA1E 1q25-q31 Brain,neuronal cells R-type LVA α1G α1H α1I CACNA1G CACNA1H CACNA1I 17q22 16p13.3 22q13 Brain Kidney, liver , heart Brain T-type T-type T-type
- 16. Receptor – OperatedChannels ( Ligand – Gated Ion Channels) • Independent of membrane depolarization • It is found on the plasma membrane • composed of 4 or 5 subunits in various combinations depending on the particular receptor.
- 17. LIGAND – GATEDION CHANNELS Type Gated by Genes Location Function IP3 receptor IP3 ITPR1, ITPR2, ITPR3 ER/SR Releases calcium from ER/SR in response to IP3 by Ryanodine receptor Dihydropyridi ne receptors in T-tubules and increased intracellular calcium (CICR) RYR1, RYR2, RYR3 ER/SR Calcium- induced calcium release in myocytes Cation channels of sperm store- operated channels indirectly by ER/SR depletion of calcium ORAI1, ORAI2, ORAI3 plasma membrane
- 18. LEAKEY Ca+2 CHANNELS • smallamount of Ca+2 leak into resting cell and pump out by Ca+2 ATPase • Mechanical stretch promotes inward movement in Ca+2 occurring through activation of leaky channels or separate stretch sensitive channels.
- 19. CHANNELOPATHIES Hypokalemic periodic paralysisVoltage-gated Na+2 or Ca+2 channel Malignant hyperthermia Ligand-gated Ca+2 channel Timothy syndrome Voltage-dependent Ca+2 channel
- 20. CHANNELOPATHIES HYPOKALEMIC PERIODIC PARALYSIS MUTATEDGENE CALCL1A3 SCN4A CHROMOSOME 1q31 17q DEFECTIVE CHANNEL CALCIUM SODIUM MODE OF INHERITENCE AUTOSOMAL DOMINANT TYPE 1 TYPE 2
- 21. CHANNELOPATHIES HYPOKALEMIC PERIODIC PARALYSIS Prevelance1:100,000 Symptoms during attacks Acute onselt flaccid paralysis Proximal >>> distal Triggers High carbohydrate, High salt, Drugs- beta agonists, Insulin Rest following prolonged exercise
- 22. CHANNELOPATHIES Malignant hyperthermia • Mutationof the ryanodine receptor (type 1), located on the sarcoplasmic reticulum , that stores calcium. • RYR1 opens in response to increases in intracellular Ca2+ level mediated by L-type • RYR1 has two sites for reacting to changing Ca2+ concentrations; A- site and the I-site.
- 23. Malignant hyperthermia Skeletal muscleRigidity and weakness Rhabdomyolysis Muscle spasms especially affecting Masseter, but can be generalised myalgia Autonomic Sympathetic overactivity Hyperventilation Tachycardia Haemodynamic instability Cardiac arrhythmia Laboratory Increased oxygen consumption Hypercapnia Lactic acidosis Raised creatine kinase Hyperkalaemia
- 24. Malignant hyperthermia Triggers Fullepisodes: general anaesthesia (inhalational agents— isoflurane, desflurane,) suxamethonium Milder malignant hyperthermia: exercise in hot conditions, neuroleptic drugs, alcohol, infections Treatment Dantrolene 2 mg/kg intravenously every 5 minutes to a total of 10 mg/kg Avoid calcium, calcium antagonists, b-blockers
- 25. Timothy syndrome • AD. •classical (type-1) and atypical (type-2). • Physical malformations, as well as neurological and developmental defects. • They are both caused by mutations in CACNA1C, the gene encoding the Ca2+ α subunit. • Mutations in CACNA1C cause delayed channel closing & thus increased cellular excitability.
- 26. THERAPEUTICS USES OFCa+2 CHANNELS • Calcium channel blockers (CCBS). • Calcium Channels role in Anesthetics. • Antiepileptic • Prophylaxis of Migraine. • Rx of infestation. • Other roles
- 27. USES OF Ca+2 CHANNELS CALIUMCHANNEL BLOCKERS
- 28. CCBS MECHANISM OFACTION • block calcium entry into cardiac and vascular smooth muscle at the alph1 subunit of the L-type voltage-gated calcium ion channels (slow channels) • Increase the time that Ca 2+ channels are closed
- 29. USES OF Ca+2 CHANNELS Ca+2 CHANNELSROLE IN ANESTHETICS
- 30. MECHANISM OF ACTION •volatile inhalational anesthetics at clinically relevant conces. inhibit inward currents through VDCCs in a dose-dependent manner without an apparent change in the time course of activation or inactivation. • The I.V anesthetics thiopental, ketamine & propofol all inhibited inward ca+2 currents through L- type VDCCs of porcine tracheal smooth muscle cells
- 31. USES OF Ca+2 CHANNELS Localanesthetics Mechanism • Lidocaine at clinically relevant conces. has been shown to inhibit inward ca+2 currents in ganglionic neurons & in frog dorsal root ganglionic cells. • Lidocaine, tetracaine & bupivacaine also inhibit the VDCC activity of cardiac myocytes in the chick, guinea pig & hamster, respectively.
- 32. USES OF Ca+2 CHANNELS AsAntiepileptic .. Valproic acid (Na valproate) Ethosuximide Absence seizures, GTCS, CPS Juvenile myoclonic epilepsy, Lennox-Gastaut syndrome, second-line treatment of status epilepticus, post-traumatic epilepsy. (neurodegenerative diseases such as Alzheimer's disease and Huntington's disease) Absence seizures Anorexia, vomiting drowsiness, ataxia Hypersensitivity rashes, blood dyscrasias. •Blocks voltage-gated sodium channels & T-type calcium channels. •Affect the function of the neurotransmitter GABA •Inhibitor of the enzyme histone deacetylase 1 Reduced low-threshold Ca2+ currents in T-type Ca2+ channels in thalamic neuron
- 33. USES OF Ca+2 CHANNELS Prophylaxisof Migraine. Flunarizine. • non-selective calcium entry blocker + histamine H1 blocking activity. • Also Na channel blocker SE; Sedation, constipation, dry mouth, wt gain, extrapyramidal effects, drowsiness.
- 34. USES OF Ca+2 CHANNELS Infestationtreatment • Praziquantel – Rx Tape worms, flukes worms. Mechanism --increases the permeability of the membranes of cells towards calcium. SE- • dizziness, headache, and malaise, drowsiness, somnolence, fatigue, and vertigo. • Urticaria, rash, pruritus
- 35. Summary • Intracellular freeca+2 is important for regulation of cell function. • Increase in concen. of intracellular free ca+2 can be obtained by rapid but transient ca+2 release from intracellular ca+2 stores & by slow ca+2 influx from the extracellular space. • VDCCS serve as one of the important mechanisms for ca+2 influx into the cells, enabling the regulation of intracellular free ca+2 concentration.
- 36. Summary L N P/QR T VA HVA HVA HVA IVA LVA location heart Neuronal Neuronal Neuronal Heart function Contraction Release Release Release Pacemaker
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Editor's Notes
- #5 An increase in intracellular calcium activates myosin light-chain kinase, resulting in phosphorylation of myosin light chain, actin-myosin interactions, and smooth muscle contraction
- #7 Insulin secretion - Insulin secretion in beta cells is triggered by rising blood glucose levels. Starting glucose by the GLUT2, t glycolytic phosphorylation of glucose COZ a rise in the ATP:ADP ratio. rise inactivates Kchannel Dat depolarizes membrane, COZ calcium channel 2 open up allowing calcium ions to flow inward. rise in levels of calcium leads to the exocytotic release of insulin from their storage granule.
- #8 The ca +2 channel can be divided into subtypes according to their electrophysiological characteristics & each subtype is encoded by its own gene
- #9 "L" stands for long-lasting referring to the length of activation P-type ('P' for cerebellar Purkinje cells) N-type ('N' for "Neural-Type" ) calcium channels are found primarily at presynaptic terminals , are involved in NT release "T" stands for transient referring to the length of activation.
- #10 low-voltage-activated (LVA) channels-activated by small depolarizations of the PM found in excitable cells ( e.g. , muscle, glial cells, neurons, etc.) high-voltage-gated calcium channels (HVGCCs). High-voltage-gated calcium channels include the neural N-type channel blocked by ω-conotoxin GVIA, R-type channel (R stands for R esistant to the other blockers and toxins, except SNX-482) involved in poorly defined processes in the brain, closely related P/Q-type channel blocked by ω-agatoxins, dihydropyridine-sensitive L-type channels responsible for excitation-contraction coupling of skeletal, smooth and cardiac muscle and for hormone secretion in endocrine cells
- #11 It is high conce. in skeletal muscle. L-type VDCCs are expressed ubiquitously in neuronal, endocrine, cardiac, smooth, & skeletal muscle, as well as in fibroblasts & kidney cells the generation of AP & to signal transduction at cell membrane L-type VDCCs in the process of neurotransmitter secretion of the central nervous system
- #12 L-type ca +2 channels are linked to ryanodine receptor of sarcoplasmic reticulum. Abnormal ryanodine receptor causes malignant hyperthermia a hypermetabolic crisis triggered by suxamethonium & volatile anesthetics.
- #13 Strong depolarization by an AP COZ channels to open & allow influx of Ca 2+ , initiating vesicle fusion & release of stored neurotransmitter. channels blocked by ω-conotoxin
- #14 Immunohistological studies Channel is widely expressed --mammalian central nervous system neuronal integration-- process by wic inhibitory & excitatory postsynaptic potentials summate & control the rate of firing of a neuron.
- #16 main subunit 1 can function as ca +2 channel. Other subunits ( 2 / & ) contribute to the regulation of a ca +2 channel function by changing drug affinity & / or voltage dependence.
- #17 the receptor-operated calcium channels (in vasoconstriction) Binding adr or others
- #18 Calcium Induced Calcium Release - (CICR) The cation channels of sperm AKA Catsper channels or CatSper , are ion channels that are related to the two-pore channels and distantly related to TRP channels. The four members of this family form voltage-gated Ca 2+ channels that seem to be specific to sperm. These channels are required for proper fertilization.The study of these channels has been slow because they do not traffic to the cell membrane in many heterologous systems. Transient receptor potential channel
- #21 mutation slows the activation rate of L-type Ca current to 30% of Normal. voltage-sensitive sodium channel gene ( SCN4A ). voltage-sensitive, skeletal muscle calcium channel gene, CALCL1A3
- #22 FIRST AND SECOND DECADE OF LIFE
- #23 A-site (high affinity Ca 2+ binding site) mediates RYR1 opening. I-site(lower affinity site ) mediates the protein's closing Caffeine, halothane, act by increasing the affinity of the A-site for Ca 2+ & decreasing t affinity of I-site in mutant proteins Ca 2+ consumes large amounts of ATP, generates the excessive heat (hyperthermia). muscle cell is damaged by the depletion of ATP , possibly high temp
- #26 QT-prolongation, heart arrhythmias, structural heart defects, syndactyly and autism spectrum disorders. Early childhood death. Calcium channel, voltage-dependent, L type, alpha 1C subunit (also known as Ca v 1.2 ) (webbing of fingers and toes) QT interval represents electrical depolarization and repolarization of the left and right ventricles. A lengthened QT interval is a biomarker for ventricular tachyarrhythmias like torsades de pointes &a risk factor for sudden death.
- #29 USES Angina pectoris Hypertension Treatment of supraventricular arrhythmias -- Atrial Flutter , Atrial Fibrillation, Paroxysmal SVT
- #30 The effects of various kinds of anesthetics in a variety of cell types have been demonstrated & a number of clinical effects of anesthetics can be explained by their effects on ca +2 channels.
- #31 Effect of these anesthetics that can account for their airway smooth muscle relaxant effects. Ikemoto first demonstrated in 1985---halothane decreased inward ca +2 slow currents in ventricular myocytes in rats Terrar reported the inhibitory effect of halothane & isoflurane on ca +2 channels of cardiac myocytes from the guinea pig ventricle.
- #33 JME 12-18 idiopathic generalized epilepsy + myoclonus occurring early in the morning LGS 2-6 TH YEAR Difficult-to-treat form of childhood-onset epilepsy + characterized frequent seizures & different seizure types + developmental delay and psychological & behavioral problems.
- #34 decrease intracellular ca release Cerbro selective ca channel blockers USES; occlusive peripheral vascular disease, vertigo of central & peripheral origin. reduce headache frequency and severity in both adults & children .
- #35 ions,induces contraction, resulting in paralysis in the contracted state. The dying parasites are dislodged from their site of action in the host organism and may enter systemic circulation or may be destroyed by host immune reaction