Calcium channels –physiology and Therapeutics uses..
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  • An increase in intracellular calcium activates myosin light-chain kinase, resulting in phosphorylation of myosin light chain, actin-myosin interactions, and smooth muscle contraction
  • 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.
  • The ca +2 channel can be divided into subtypes according to their electrophysiological characteristics & each subtype is encoded by its own gene
  • "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.
  • 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
  • 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
  • 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.
  • 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
  • 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.
  • 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.
  • the receptor-operated calcium channels (in vasoconstriction) Binding adr or others
  • 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
  • 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
  • FIRST AND SECOND DECADE OF LIFE
  • 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
  • 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.
  • USES Angina pectoris Hypertension Treatment of supraventricular arrhythmias -- Atrial Flutter , Atrial Fibrillation, Paroxysmal SVT
  • 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.
  • 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.
  • 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.
  • 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 .
  • 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

Transcript

  • 1. Calcium channels physiologyand Therapeutics uses..Dr . Kapil Dev Doddamani.
  • 2. • Function.• Types of Calcium channels.• Channelopathies.• Therapeutics Uses of Calcium .
  • 3. Function• Signal transduction pathways, second messenger• Neurotransmitter release from neurons• Contraction of all muscle cell types• Many enzymes require calcium ions as a cofactor (blood-clottingcascade)• Extracellular calcium is also important for maintaining the potentialdifference across excitable cell membranes, as well as proper boneformation.•
  • 4. Function
  • 5. Ventricular AP Function• Phase 4: resting membranepotential near the K+equilibrium potential.• Phase 0: depolarizing impulseactivates fast Na+channelsand inactivates K+channels.• Phase 1: Transient opening ofK+channels and Na+channelsbegin to close.• Phase 2: Ca2+channels areopen, key difference betweennerve AP.• Phase 3: repolarization, Ca2+inactivate and K+channelsopen.• Refractory period: Na+channels are inactive untilmembrane is repolarized.
  • 6. FUNCTIONThe synthesis and release ofinsulin is modulated by:1. Glucose (mostimportant), AAs, FAsand ketone bodiesstimulate release.2. Glucagon andsomatostation inhibitrelases3. α-Adrenergicstimulation inhibitsrelease (mostimportant).4. β-Adrenergicstimulation promotesrelease.5. Elevated intracellularCa2+promotes release.Example of how an endocrine cell(pancreatic β-cell) depolarizes itsmembrane with Ca2+to releaseinsulin.
  • 7. Classes of Ca+2channels– Voltage- Sensitive (VDCCs)– Receptor- Operated (Ligand- Gated ion channels)– Leakey channels
  • 8. VDCCs• The possible existence of VDCCs was first reported byHagiwara in 1975 using egg cell membrane of a starfish.• They were initially divided into 2 classes HVA & LVA ca+2channels.• HVA ca+2channels are further divided into L,N,P/Q & R-typeschannels,• LVA ca+2channels consists of only T-type channels.• R-type is occasionally classified as ( IV A ) channels.
  • 9. Structure & FunctionL-TYPE Ca+2CHANNEL• It is composed of 5 different polypeptide subunits, different molmassesι. α1(175KD) , which forms the ion channel & contains ca+2antagonist binding sites.ιι. α2(143KD), which is associated with α1 & does not contain anyhigh-affinity binding site.ιιι.β(54KD),ιϖ.γ(30KD),ϖ. δ(27KD).
  • 10. L-TYPE Ca+2CHANNEL
  • 11. N-TYPE Ca+2CHANNEL• It is purified from the rat brain.• It is composed of 4 subunits:∀ α1 , α2 , γ , & β.• role -- neurotransmitter release.
  • 12. P/Q-TYPE Ca+2CHANNEL• It is composed of α1, α2, δ & β subunits.• Play similar role - N-type calcium channel (NT release at e presynapticterminal & neuronal integration in many neuronal types.• They are also found in Purkinje fibers in the electrical conduction system ofthe heart.• P channels were discovered in cerebellar Purkinje cells by Llinas andSugimo
  • 13. T-TYPE Ca+2CHANNEL• T-type VDCCs are activated at negative membrane potentialsclose to the resting potential.• the T-type channel is thought to be responsible for neuronaloscillatory activity, which is proposed to be involved in processsuch as sleep / wakefulness regulation & motor coordination.• In addition ,T-type ca+2channels are involved in pacemakeractivity.
  • 14. CHANNEL GENEIsoform Gene name ChromosomallocalizationTissuedistributionBiophysicalpropertiesHVAα1Aα1Bα1Cα1Dα1Fα1SCACNA1ACACNA1BCACNA1CCACNA1DCACNA1FCACNA1S19p13.1-29q3412p13.33p14.3Xp11.231q31-q32Brain,neuronalcells,heartBrain,neuronalcellsUbiquitousBrain,neuronal,cells,endocrine cellsSkeletal muscleP / Q –typeN-typeL-typeL-typeL-typeL-typeIVAα1ECACNA1E 1q25-q31 Brain,neuronalcellsR-typeLVAα1Gα1Hα1ICACNA1GCACNA1HCACNA1I17q2216p13.322q13BrainKidney, liver ,heartBrainT-typeT-typeT-type
  • 15. Receptor – Operated Channels( Ligand – Gated Ion Channels)• Independent of membrane depolarization• It is found on the plasma membrane• composed of 4 or 5 subunits in various combinations dependingon the particular receptor.
  • 16. LIGAND – GATED ION CHANNELSType Gated by Genes Location FunctionIP3 receptor IP3ITPR1,ITPR2,ITPR3 ER/SRReleasescalcium fromER/SR inresponse toIP3 byRyanodinereceptorDihydropyridine receptorsin T-tubulesandincreasedintracellularcalcium(CICR)RYR1,RYR2,RYR3ER/SR Calcium-inducedcalciumrelease inmyocytesCationchannels ofspermstore-operatedchannelsindirectly byER/SRdepletion ofcalciumORAI1,ORAI2,ORAI3plasmamembrane
  • 17. LEAKEY Ca+2CHANNELS• small amount of Ca+2 leak into resting cell and pump out byCa+2 ATPase• Mechanical stretch promotes inward movement in Ca+2occurring through activation of leaky channels or separatestretch sensitive channels.
  • 18. CHANNELOPATHIESHypokalemic periodic paralysis Voltage-gated Na+2orCa+2channelMalignant hyperthermia Ligand-gated Ca+2channelTimothy syndrome Voltage-dependent Ca+2channel
  • 19. CHANNELOPATHIESHYPOKALEMIC PERIODIC PARALYSISMUTATED GENE CALCL1A3 SCN4ACHROMOSOME 1q31 17qDEFECTIVECHANNELCALCIUM SODIUMMODE OFINHERITENCEAUTOSOMAL DOMINANTTYPE 1 TYPE 2
  • 20. CHANNELOPATHIESHYPOKALEMIC PERIODIC PARALYSISPrevelance 1:100,000Symptoms during attacks Acute onselt flaccid paralysisProximal >>> distalTriggers High carbohydrate,High salt,Drugs- beta agonists,InsulinRest following prolonged exercise
  • 21. CHANNELOPATHIESMalignant hyperthermia• Mutation of the ryanodine receptor (type 1), located on thesarcoplasmic reticulum , that stores calcium.• RYR1 opens in response to increases in intracellular Ca2+levelmediated by L-type• RYR1 has two sites for reacting to changing Ca2+concentrations; A-site and the I-site.
  • 22. Malignant hyperthermiaSkeletal muscle Rigidity and weaknessRhabdomyolysisMuscle spasms especiallyaffecting Masseter, but canbe generalisedmyalgiaAutonomic Sympathetic overactivityHyperventilationTachycardiaHaemodynamic instabilityCardiac arrhythmiaLaboratory Increased oxygen consumptionHypercapniaLactic acidosisRaised creatine kinaseHyperkalaemia
  • 23. Malignant hyperthermiaTriggers Full episodes: general anaesthesia (inhalationalagents— isoflurane, desflurane,) suxamethoniumMilder malignant hyperthermia: exercise in hotconditions, neuroleptic drugs, alcohol, infectionsTreatment Dantrolene 2 mg/kg intravenously every 5 minutes toa total of 10 mg/kgAvoid calcium, calcium antagonists, b-blockers
  • 24. Timothy syndrome• AD.• classical (type-1) and atypical (type-2).• Physical malformations, as well as neurological and developmentaldefects.• They are both caused by mutations in CACNA1C, the geneencoding the Ca2+α subunit.• Mutations in CACNA1C cause delayed channel closing & thusincreased cellular excitability.
  • 25. THERAPEUTICS USES OF Ca+2CHANNELS• Calcium channel blockers (CCBS).• Calcium Channels role in Anesthetics.• Antiepileptic• Prophylaxis of Migraine.• Rx of infestation.• Other roles
  • 26. USES OF Ca+2CHANNELSCALIUM CHANNEL BLOCKERS
  • 27. CCBS MECHANISM OF ACTION• block calcium entry into cardiac and vascular smooth muscle atthe alph1 subunit of the L-type voltage-gated calcium ionchannels (slow channels)• Increase the time that Ca 2+channels are closed
  • 28. USES OF Ca+2CHANNELSCa+2CHANNELS ROLE IN ANESTHETICS
  • 29. MECHANISM OF ACTION• volatile inhalational anesthetics at clinically relevant conces. inhibitinward currents through VDCCs in a dose-dependent mannerwithout an apparent change in the time course of activation orinactivation.• The I.V anesthetics thiopental, ketamine & propofol all inhibitedinward ca+2 currents through L- type VDCCs of porcine trachealsmooth muscle cells
  • 30. USES OF Ca+2CHANNELSLocal anestheticsMechanism• Lidocaine at clinically relevant conces. has been shown to inhibitinward ca+2currents in ganglionic neurons & in frog dorsal rootganglionic cells.• Lidocaine, tetracaine & bupivacaine also inhibit the VDCC activity ofcardiac myocytes in the chick, guinea pig & hamster, respectively.
  • 31. USES OF Ca+2CHANNELSAs Antiepileptic ..Valproic acid (Na valproate) EthosuximideAbsence seizures, GTCS, CPSJuvenile myoclonic epilepsy,Lennox-Gastaut syndrome,second-line treatment of statusepilepticus,post-traumatic epilepsy.(neurodegenerative diseases such asAlzheimers disease and Huntingtonsdisease)Absence seizuresAnorexia, vomiting drowsiness, ataxia Hypersensitivity rashes, blooddyscrasias.•Blocks voltage-gated sodium channels& T-type calcium channels.•Affect the function of theneurotransmitter GABA•Inhibitor of the enzyme histonedeacetylase 1Reduced low-threshold Ca2+currents inT-type Ca2+channels in thalamic neuron
  • 32. USES OF Ca+2CHANNELSProphylaxis of Migraine.Flunarizine.• non-selective calcium entry blocker + histamine H1 blockingactivity.• Also Na channel blockerSE; Sedation, constipation, dry mouth, wt gain, extrapyramidaleffects, drowsiness.
  • 33. USES OF Ca+2CHANNELSInfestation treatment• Praziquantel– Rx Tape worms, flukes worms.Mechanism --increases the permeability of the membranes of cellstowards calcium.SE-• dizziness, headache, and malaise, drowsiness, somnolence,fatigue, and vertigo.• Urticaria, rash, pruritus
  • 34. Summary• Intracellular free ca+2is important for regulation of cell function.• Increase in concen. of intracellular free ca+2can be obtained byrapid but transient ca+2release from intracellular ca+2stores & byslow ca+2influx from the extracellular space.• VDCCS serve as one of the important mechanisms for ca+2influxinto the cells, enabling the regulation of intracellular free ca+2concentration.
  • 35. SummaryL N P/Q R TVA HVA HVA HVA IVA LVAlocation heart Neuronal Neuronal Neuronal Heartfunction Contraction Release Release Release Pacemaker
  • 36. The end..Thanks.