Voltage-dependent calcium channels are a group of voltage-gated ion channels
found in the membrane of excitable cells with a permeability to the calcium ion
Ca2+. These channels are slightly permeable to sodium ions, so they are
also called Ca2+-Na+ channels, but their permeability to calcium is about
1000-fold greater than to sodium under normal physiological conditions. At
physiologic or resting membrane potential, VDCCs are normally closed.
They are activated at depolarized membrane potentials and this is the
source of the "voltage-dependent" epithet. The concentration of calcium is
normally several thousand times higher outside of the cell than inside.
Activation of particular VDCCs allows Ca2+ to rush into the cell, which,
depending on the cell type, results in activation of calcium-sensitive
potassium channels, muscular contraction, excitation of neurons,
up-regulation of gene expression, or release of hormones or
neurotransmitters. VDCCs have been immunolocalized in the zona glomerulosa
of normal and hyperplastic human adrenal, as well as in
aldosterone-producing adenomas, and in the latter T-type VDCCs correlated with
plasma aldosterone levels of patients. Excessive activation of VDCCs is a major
component of excitotoxicity, as severely elevated levels of intracellular calcium
activates enzymes which, at high enough levels, can degrade essential cellular
structures. Structure
Voltage-dependent calcium channels are formed as a complex of several different
subunits: α1, α2δ, β1-4, and γ. The α1 subunit forms the ion conducting pore
while the associated subunits have several functions including modulation
of gating. Channel subunits
There are several different kinds of high-voltage-gated calcium channels.
They are structurally homologous among varying types; they are all similar, but
not structurally identical. In the laboratory, it is possible to tell them
apart by studying their physiological roles and/or inhibition by specific
toxins. High-voltage-gated calcium channels include the neural N-type
channel blocked by ω-conotoxinGVIA, the R-type channel involved in poorly
defined processes in the brain, the closely related P/Q-type channel blocked
by ω-agatoxins, and the dihydropyridine-sensitive L-type
channels responsible for excitation-contraction coupling of
skeletal, smooth, and cardiac muscle and for hormone secretion in endocrine
cells. = α1 Subunit=
The α1 subunit pore is the primary subunit necessary for channel
functioning in the HVGCC, and consists of the characteristic four homologous
I–IV domains containing six transmembrane α-helices each. The α1
subunit forms the Ca2+ selective pore, which contains voltage-sensing machinery
and the drug/toxin-binding sites. A total of ten α1 subunits that have been
identified in humans: α1 subunit contains 4 homologous domains, each
containing 6 transmembrane helices. This arrangement is analogous to a
homo-tetramer formed by single-domain subunits of voltage-gated potassium
channels. The 4-domain architecture is also shared by the voltage gated sodium
channels, which are thought to be evolutionary related to VDCCs. The
transmembrane helices from the 4 domains line up to form the channel proper; S5
and S6 helices are thought to line the inner pore surface, while S1–4 helices
have roles in gating and voltage sensing. VDCCs are subject to rapid
inactivation, which is thought to consist of 2 components:
voltage-dependent and calcium-dependent. These are distinguished by using either
Ba2+ or Ca2+ as the charge carrier in the external recording solution. The CDI
component is attributed to the binding of the Ca2+-binding signaling protein
calmodulin to at least 1 site on the channel, as Ca2+-null CaM mutants
abolish CDI in L-type channels. Not all channels exhibit the same regulatory
properties and the specific details of these mechanisms are still largely
unknown. = α2δ Subunit=
The α2δ gene forms two subunits: α2 and δ. They are linked to each other via a
disulfide bond and have a combined molecular weight of 170 kDa. The α2 is
the extracellular glycosylated subunit that interacts the most with the α1
subunit. The δ subunit has a single transmembrane region with a short
intracellular portion, which serves to anchor the protein in the plasma
membrane. There are 4 α2δ genes: CACNA2D1,
CACNA2D2, (CACNA2D3),
(CACNA2D4). Co-expression of the α2δ enhances the
level of expression of the α1 subunit and causes an increase in current
amplitude, faster activation and inactivation kinetics and a
hyperpolarizing shift in the voltage dependence of inactivation. Some of
these effects are observed in the absence of the beta subunit, whereas, in
other cases, the co-expression of beta is required.
The α2δ-1 and α2δ-2 subunits are the binding site for at least two
anticonvulsant drugs, gabapentin and pregabalin, that also find use in
treating chronic neuropathic pain. The α2δ subunit is also a binding site of
the central depressant and anxiolytic drug phenibut, in addition to actions at
other targets. = β Subunit=
The intracellular β subunit is an intracellular MAGUK-like protein
containing a guanylate kinase domain and an SH3 domain. The guanylate kinase
domain of the β subunit binds to the α1 subunit I-II cytoplasmic loop and
regulates HVGCC activity. There are four known isoforms of the β subunit:
CACNB1, CACNB2,
CACNB3, CACNB4.
It is hypothesized that the cytosolic β subunit has a major role in stabilizing
the final α1 subunit conformation and delivering it to the cell membrane by
its ability to mask an endoplasmic reticulum retention signal in the α1
subunit. The endoplasmic retention brake is contained in the I–II loop in the α1
subunit that becomes masked when the β subunit binds. Therefore the β subunit
functions initially to regulate the current density by controlling the
amount of α1 subunit expressed at the cell membrane.
In addition to this trafficking role, the β subunit has the added important
functions of regulating the activation and inactivation kinetics, and
hyperpolarizing the voltage-dependence for activation of the α1 subunit pore,
so that more current passes for smaller depolarizations. The β subunit has
effects on the kinetics of the cardiac α1C in Xenopus laevis oocytes
co-expressed with β subunits. The β subunit acts as an important modulator
of channel electrophysiological properties.
Until very recently, the interaction between a highly conserved 18-amino acid
region on the α1 subunit intracellular linker between domains I and II and a
region on the GK domain of the β subunit was thought to be solely responsible for
the regulatory effects by the β subunit. Recently, it has been discovered that
the SH3 domain of the β subunit also gives added regulatory effects on
channel function, opening the possibility of the β subunit having
multiple regulatory interactions with the α1 subunit pore. Furthermore, the
AID sequence does not appear to contain an endoplasmic reticulum retention
signal, and this may be located in other regions of the I–II α1 subunit linker.
= γ Subunit= The γ1 subunit is known to be associated
with skeletal muscle VGCC complexes, but the evidence is inconclusive regarding
other subtypes of calcium channel. The γ1 subunit glycoprotein is composed of
four transmembrane spanning helices. The γ1 subunit does not affect trafficking,
and, for the most part, is not required to regulate the channel complex.
However, γ2, γ3, γ4 and γ8 are also associated with AMPA glutamate
receptors. There are 8 genes for gamma subunits:
γ1, γ2,
γ3, γ4,
(CACNG5), (CACNG6),
(CACNG7), and (CACNG8).
= Muscle Physiology= When a smooth muscle cell is
depolarized, it causes opening of the voltage-gated calcium channels.
Depolarization may be brought about by stretching of the cell, agonist-binding
its G protein-coupled receptor, or autonomic nervous system stimulation.
Opening of the L-type calcium channel causes influx of extracellular Ca2+,
which then binds calmodulin. The activated calmodulin molecule activates
myosin light-chain kinase, which phosphorylates the myosin in thick
filaments. Phosphorylated myosin is able to form crossbridges with actin thin
filaments, and the smooth muscle fiber contracts via the sliding filament
mechanism.. L-type calcium channels are also
enriched in the t-tubules of striated muscle cells, i.e., skeletal and cardiac
myofibers. When these cells are depolarized, the L-type calcium channels
open as in smooth muscle. In skeletal muscle, the actual opening of the
channel, which is mechanically gated to a calcium-release channel in the
sarcoplasmic reticulum, causes opening of the RYR. In cardiac muscle, opening
of the L-type calcium channel permits influx of calcium into the cell. The
calcium binds to the calcium release channels in the SR, opening them; this
phenomenon is called "calcium-induced calcium release", or CICR. However the
RYRs are opened, either through mechanical-gating or CICR, Ca2+ is
released from the SR and is able to bind to troponin C on the actin filaments.
The muscles then contract through the sliding filament mechanism, causing
shortening of sarcomeres and muscle contraction.
See also Glutamate receptors
Inositol triphosphate receptor Ion channels
NMDA receptors Ryanodine receptor
Voltage-gated ion channels Gabapentin
Pregabalin References
External links Andrea Welling: Voltage-Dependent
Calcium Channels, BIOTREND Reviews No. 04, January 2009, 2009 BIOTREND
Chemicals AG "Voltage-Gated Ion Channels". IUPHAR
Database of Receptors and Ion Channels. International Union of Basic and
Clinical Pharmacology. Calcium Channels at the US National
Library of Medicine Medical Subject Headings