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Calcium channels physiology and Therapeutics uses..
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Calcium channels physiology and 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-clotting
cascade)
• Extracellular calcium is also important for maintaining the potential
difference across excitable cell membranes, as well as proper bone
formation.
•
Function
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.
FUNCTION
The synthesis and release 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 itsmembrane with Ca2+ to release insulin.
Classes of Ca+2 channels
– Voltage- Sensitive (VDCCs)
– Receptor- Operated (Ligand- Gated ion channels)
– Leakey channels
VDCCs
• The possible existence 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.
Structure & Function
L-TYPE Ca+2 CHANNEL
• It is composed of 5 different polypeptide subunits, different mol
masses
i. 1(175KD) , which forms the ion channel & contains ca+2
antagonist binding sites.
ii. 2(143KD), which is associated with 1 & does not contain any
high-affinity binding site.
iii.(54KD),
iv.(30KD),
v. (27KD).
L-TYPE Ca+2 CHANNEL
N-TYPE Ca+2 CHANNEL
• It is purified from the rat brain.
• It is composed of 4 subunits:
1 , 2 , , & .
• role -- neurotransmitter release.
P/Q-TYPE Ca+2 CHANNEL• It is composed of 1, 2, & 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
T-TYPE Ca+2 CHANNEL
• T-type VDCCs 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.
CHANNEL GENEIsoform Gene name Chromosomal
localization
Tissue distribution
Biophysical
properties
HVA1A
1B
1C
1D
1F
1S
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,cells,endocrine cells
Skeletal muscle
P / Q –type
N-type
L-type
L-type
L-type
L-type
IVA1E CACNA1E 1q25-q31 Brain,neuronal
cellsR-type
LVA1G
1H
1I
CACNA1G
CACNA1H
CACNA1I
17q22
16p13.3
22q13
Brain
Kidney, liver , heart
Brain
T-type
T-type
T-type
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 depending
on the particular receptor.
LIGAND – GATED ION 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
Dihydropyridine 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
LEAKEY Ca+2 CHANNELS
• small amount 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.
CHANNELOPATHIES
Hypokalemic periodic paralysis Voltage-gated Na+2 or Ca+2 channel
Malignant hyperthermia Ligand-gated Ca+2 channel
Timothy syndrome Voltage-dependent Ca+2 channel
CHANNELOPATHIES
HYPOKALEMIC PERIODIC PARALYSIS
MUTATED GENE CALCL1A3 SCN4A
CHROMOSOME 1q31 17q
DEFECTIVE CHANNEL
CALCIUM SODIUM
MODE OF INHERITENCE
AUTOSOMAL DOMINANT
TYPE 1 TYPE 2
CHANNELOPATHIES HYPOKALEMIC PERIODIC PARALYSIS
Prevelance 1:100,000
Symptoms during attacks Acute onselt flaccid paralysisProximal >>> distal
Triggers High carbohydrate,High salt, Drugs- beta agonists,InsulinRest following prolonged exercise
CHANNELOPATHIES
Malignant hyperthermia
• Mutation of 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.
Malignant hyperthermiaSkeletal muscle Rigidity and weakness
RhabdomyolysisMuscle spasms especially affecting Masseter, but canbe generalisedmyalgia
Autonomic Sympathetic overactivityHyperventilationTachycardiaHaemodynamic instabilityCardiac arrhythmia
Laboratory Increased oxygen consumptionHypercapniaLactic acidosisRaised creatine kinaseHyperkalaemia
Malignant hyperthermiaTriggers Full episodes: general anaesthesia (inhalational
agents— isoflurane, desflurane,) suxamethoniumMilder malignant hyperthermia: exercise in hotconditions, neuroleptic drugs, alcohol, infections
Treatment 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 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.
THERAPEUTICS USES OF Ca+2 CHANNELS
• Calcium channel blockers (CCBS).
• Calcium Channels role in Anesthetics.
• Antiepileptic
• Prophylaxis of Migraine.
• Rx of infestation.
• Other roles
USES OF Ca+2 CHANNELS
CALIUM CHANNEL BLOCKERS
CCBS MECHANISM OF ACTION
• 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
USES OF Ca+2 CHANNELS
Ca+2 CHANNELS ROLE IN ANESTHETICS
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
USES OF Ca+2 CHANNELS
Local anesthetics
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.
USES OF Ca+2 CHANNELS
As Antiepileptic ..Valproic acid (Na valproate) Ethosuximide
Absence seizures, GTCS, CPSJuvenile 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
USES OF Ca+2 CHANNELS
Prophylaxis of 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.
USES OF Ca+2 CHANNELS
Infestation treatment• 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
Summary
• Intracellular free ca+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.
Summary L N P/Q R T
VA HVA HVA HVA IVA LVA
location heart Neuronal Neuronal Neuronal Heart
function Contraction Release Release Release Pacemaker
The end..
Thanks.