Calcium channels physiologyand Therapeutics uses..Dr . Kapil Dev Doddamani.
• Function.• Types of Calcium channels.• Channelopathies.• Therapeutics Uses of Calcium .
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.•
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.
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.
Classes of Ca+2channels– Voltage- Sensitive (VDCCs)– Receptor- Operated (Ligand- Gated ion channels)– Leakey channels
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.
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).
N-TYPE Ca+2CHANNEL• It is purified from the rat brain.• It is composed of 4 subunits:∀ α1 , α2 , γ , & β.• role -- neurotransmitter release.
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
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.
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.
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.
CHANNELOPATHIESHYPOKALEMIC PERIODIC PARALYSISPrevelance 1:100,000Symptoms during attacks Acute onselt flaccid paralysisProximal >>> distalTriggers High carbohydrate,High salt,Drugs- beta agonists,InsulinRest following prolonged exercise
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.
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
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.
THERAPEUTICS USES OF Ca+2CHANNELS• Calcium channel blockers (CCBS).• Calcium Channels role in Anesthetics.• Antiepileptic• Prophylaxis of Migraine.• Rx of infestation.• Other roles
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
USES OF Ca+2CHANNELSCa+2CHANNELS ROLE IN ANESTHETICS
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
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.
USES OF Ca+2CHANNELSAs Antiepileptic ..Valproic acid (Na valproate) EthosuximideAbsence seizures, GTCS, CPSJuvenile 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
USES OF Ca+2CHANNELSProphylaxis of Migraine.Flunarizine.• non-selective calcium entry blocker + histamine H1 blockingactivity.• Also Na channel blockerSE; Sedation, constipation, dry mouth, wt gain, extrapyramidaleffects, drowsiness.
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
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.
SummaryL N P/Q R TVA HVA HVA HVA IVA LVAlocation heart Neuronal Neuronal Neuronal Heartfunction Contraction Release Release Release Pacemaker