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.

1. Calcium channels physiology
and 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-clotting
cascade)
• Extracellular calcium is also important for maintaining the potential
difference across excitable cell membranes, as well as proper bone
formation.
•

4. Function

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 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 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 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.

10. Structure & Function
L-TYPE Ca+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).

11. L-TYPE Ca+2
CHANNEL

12. N-TYPE Ca+2
CHANNEL
• It is 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
• It is 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-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.

15. CHANNEL GENE
Isoform Gene name 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 – 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.

17. 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
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
• 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.

19. 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

20. CHANNELOPATHIES
HYPOKALEMIC PERIODIC PARALYSIS
MUTATED GENE CALCL1A3 SCN4A
CHROMOSOME 1q31 17q
DEFECTIVE
CHANNEL
CALCIUM SODIUM
MODE OF
INHERITENCE
AUTOSOMAL DOMINANT
TYPE 1 TYPE 2

21. CHANNELOPATHIES
HYPOKALEMIC PERIODIC PARALYSIS
Prevelance 1:100,000
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
• 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.

23. Malignant hyperthermia
Skeletal muscle Rigidity 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 Full episodes: 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 OF Ca+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
CALIUM CHANNEL BLOCKERS

28. 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

29. USES OF Ca+2
CHANNELS
Ca+2
CHANNELS ROLE 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
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.

32. USES OF Ca+2
CHANNELS
As Antiepileptic ..
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
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.

34. 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

35. 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.

36. 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

37. The end..
Thanks.