Biomedical Engineering Reference
In-Depth Information
2 Overview of Neuronal Voltage-Gated Ca
2+
Channels
Neuronal VGCCs are group of large multi-subunit ion channels with permeability to
the ion Ca
2+
in response to membrane potential changes due to excitation of neurons
[
27
]. They constitute one of a group of superfamily of ion channels showing
sequence, topological and functional similarity [
28
]. These ion channels are
designated as voltage dependent in response to activation (open state) at depolarized
or inactivation (close state) at polarized membrane potentials. Excited neuronal cells
allow the entry of Ca
2+
in response to membrane depolarization, resulting in
muscular contraction, hormone and neuro-transmitter release, cellular motility,
cellular growth and regulation, cellular damage and death and finally its survival.
VGCCs are well-studied membrane proteins and lot of information was avail-
able using electrophysiological, biochemical, pharmacological, and molecular biol-
ogy techniques. Based on the pharmacological studies, further categorization of the
channel family into L-, N-, P-, Q-, R-, and T- has been done. Also, in accordance
with the electrophysiological nature, these channels are classified into two types: (a)
high voltage-activated channels belonging to L-, N-, P-/Q-, and R-types, and
require higher depolarization current to be activated; (b) low voltage-activated
channel belonging to T-type which requires lower depolarization current to be
activated. These ion channels differ in function, activation/inactivation voltage,
conductance and sensitivity toward various drugs and toxins [
29
-
31
].
The biochemical and pharmacological significance of these five ion channels
toward disease cause is also well known. (a) L-type Ca
2+
channels (LCCs) have
high activation threshold and have four subunit genes - Ca
v
1.1, Ca
v
1.2, Ca
v
1.3, and
Ca
v
1.4 (
a
1F
). These channels express in neurons, endocrine,
skeletal muscle, and cardiovascular system, mainly responsible for cardiac
disorders. Specific LCC blockers are discovered, which include different classes
such as dihydropyridines, phenylalkylamines, and benzothiazepines. (b) P- and
Q-type Ca
2+
channels (P/Q CCs) have high activation threshold and have one subunit
gene - Ca
v
2.1 (
a
1C
,
a
1D
,
a
1S
and
a
1A
). These channels mainly express in neurons, and was responsi-
ble for epilepsy and migraine symptoms. Specific P/QCC blockers are discovered,
which include
-conotoxin GVIA. (c)
NCCs have high activation threshold and have one subunit gene - Ca
v
2.2 (
o
-agatoxin IVA,
o
-conotoxin MVIIC and
o
a
1B
).
These channels mainly express in neurons, and was responsible for pain symptoms.
Specific NCC blockers are discovered, which include
-conotoxin MVIIA, Prialt
®
and AM336. (d) R-type Ca
2+
channels (RCCs) have high activation threshold and
have one subunit gene - Ca
v
2.3 (
o
a
1E
). These channels mainly express in neurons,
and were responsible for diabetes symptoms. SNX-482 is a clinically validated
specific RCC blocker. (e) T-type Ca
2+
channels (TCCs) have low activation thresh-
old and have three subunit genes - Ca
v
3.1, Ca
v
3.2, and Ca
v
3.3 (
a
1I
).
These channels mainly expresses in neurons, smooth muscle and sinoatrial node,
and were responsible for arrhythmias, epilepsy, and pain. Specific TCC blockers are
discovered, which include nickel ethosuximide, zonisamide, mibefradil, and
kurotoxin.
a
1G
,
a
1H
,and
