Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of
voltage-gated ion channels found in the
membrane
A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. ...
of excitable cells (''e.g.'',
muscle,
glial cell
Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form myel ...
s,
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
s, etc.) with a
permeability to the
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
ion Ca
2+.
These channels are slightly permeable to
sodium ions, so they are also called Ca
2+-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, VGCCs are normally closed. They are activated (''i.e.'': opened) at
depolarized membrane potentials and this is the source of the "voltage-gated"
epithet. The concentration of
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
(Ca
2+ ions) is normally several thousand times higher outside the cell than inside. Activation of particular VGCCs allows a Ca
2+ influx into the cell, which, depending on the cell type, results in activation of calcium-sensitive
potassium channel
Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of c ...
s,
muscular contraction
Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as ...
,
excitation of neurons, up-regulation of
gene expression, or release of
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are require ...
s or
neurotransmitters.
VGCCs have been immunolocalized in the
zona glomerulosa
The ''zona glomerulosa'' (sometimes, glomerular zone) of the adrenal gland is the most superficial layer of the adrenal cortex, lying directly beneath the renal capsule. Its cells are ovoid and arranged in clusters or arches (''glomus'' is Latin ...
of normal and hyperplastic human
adrenal
The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex whic ...
, as well as in
aldosterone-producing
adenomas (APA), and in the latter T-type VGCCs correlated with plasma aldosterone levels of patients.
Excessive activation of VGCCs is a major component of
excitotoxicity
In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate ...
, as severely elevated levels of intracellular calcium activates enzymes which, at high enough levels, can degrade essential cellular structures.
Structure
Voltage-gated calcium channels are formed as a complex of several different subunits: α
1, α
2δ, β
1-4, and γ. The α
1 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 (HVGCCs). 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
toxin
A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849 ...
s. High-voltage-gated calcium channels include the
neural N-type channel blocked by ω-
conotoxin
A conotoxin is one of a group of neurotoxic peptides isolated from the venom of the marine cone snail, genus ''Conus''.
Conotoxins, which are peptides consisting of 10 to 30 amino acid residues, typically have one or more disulfide bonds. Cono ...
GVIA, the R-type channel (R stands for Resistant to the other blockers and toxins, except
SNX-482 SNX-482 is a toxin from the tarantula ''Hysterocrates gigas''. It acts as a high-affinity blocker of R-type Ca2+ (Cav2.3) channels, but at higher concentrations it can also block other Ca2+ channels and Na+ channels.
Sources
SNX-482 is isolated ...
) involved in poorly defined processes in the
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...
, the closely related P/Q-type channel blocked by ω-
agatoxin
Agatoxins are a class of chemically diverse polyamine and peptide toxins which are isolated from the venom of various spiders. Their mechanism of action includes blockade of glutamate receptor, glutamateligand-gated ion channel, -gated ion channel ...
s, and the dihydropyridine-sensitive L-type channels responsible for excitation-contraction coupling of
skeletal,
smooth
Smooth may refer to:
Mathematics
* Smooth function, a function that is infinitely differentiable; used in calculus and topology
* Smooth manifold, a differentiable manifold for which all the transition maps are smooth functions
* Smooth algebrai ...
, and
cardiac muscle
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...
and for hormone secretion in endocrine cells.
Reference for the table can be found at Dunlap, Luebke and Turner (1995).
α1 Subunit
The α
1 subunit pore (~190 kDa in molecular mass) 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 α
1 subunit forms the Ca
2+ selective pore, which contains voltage-sensing machinery and the drug/toxin-binding sites. A total of ten α
1 subunits that have been identified in humans:
α
1 subunit contains 4 homologous domains (labeled I–IV), each containing 6 transmembrane helices (S1–S6). This arrangement is analogous to a homo-tetramer formed by single-domain subunits of voltage-gated potassium channels (that also each contain 6 TM helices). The 4-domain architecture (and several key regulatory sites, such as the EF hand and IQ domain at the C-terminus) is also shared by the voltage gated sodium channels, which are thought to be evolutionarily related to VGCCs. 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 (S4 in particular). VGCCs are subject to rapid inactivation, which is thought to consist of 2 components: voltage-gated (VGI) and calcium-gated (CGI). These are distinguished by using either Ba
2+ or Ca
2+ as the charge carrier in the external recording solution (''in vitro''). The CGI component is attributed to the binding of the Ca
2+-binding signaling protein
calmodulin (CaM) to at least 1 site on the channel, as Ca
2+-null CaM mutants abolish CGI 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 α
2δ gene forms two subunits: α
2 and δ (which are both the product of the same gene). They are linked to each other via a disulfide bond and have a combined molecular weight of 170 kDa. The α
2 is the extracellular glycosylated subunit that interacts the most with the α
1 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 α
2δ genes:
*
CACNA2D1 (),
*
CACNA2D2 (),
* (),
* ().
Co-expression of the α
2δ enhances the level of expression of the α
1 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 α
2δ-1 and α
2δ-2 subunits are the binding site for
gabapentinoid
Gabapentinoids, also known as α2δ ligands, are a class of drugs that are derivatives of the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA) (i.e., GABA analogues) which block α2δ subunit-containing voltage-dependent calcium ch ...
s. This drug class includes two anticonvulsant drugs,
gabapentin
Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat partial seizures and neuropathic pain. It is a first-line medication for the treatment of neuropathic pain caused by diabeti ...
(Neurontin) and
pregabalin
Pregabalin, sold under the brand name Lyrica among others, is an anticonvulsant, analgesic and anxiolytic medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome, opioid withdrawal and generalized anxiety diso ...
(Lyrica), that also find use in treating chronic neuropathic pain. The α
2δ subunit is also a binding site of the central depressant and
anxiolytic
An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiet ...
phenibut, in addition to actions at other targets.
β Subunit
The intracellular β subunit (55 kDa) is an intracellular MAGUK-like protein (Membrane-Associated Guanylate Kinase) containing a guanylate kinase (GK) domain and an SH3 (src homology 3) domain. The guanylate kinase domain of the β subunit binds to the α
1 subunit I-II cytoplasmic loop and regulates HVGCC activity. There are four known genes for the β subunit:
*
CACNB1
Voltage-dependent L-type calcium channel subunit beta-1 is a protein that in humans is encoded by the ''CACNB1'' gene.
The protein encoded by this gene belongs to the calcium channel beta subunit family. It plays an important role in the calcium ...
(),
*
CACNB2
Voltage-dependent L-type calcium channel subunit beta-2 is a protein that in humans is encoded by the ''CACNB2'' gene.
Clinical significance
Mutation in the CACNB2 gene are associated with Brugada syndrome, autism, attention deficit-hyperac ...
(),
*
CACNB3 (),
*
CACNB4 ().
It is hypothesized that the cytosolic β subunit has a major role in stabilizing the final α
1 subunit conformation and delivering it to the cell membrane by its ability to mask an
endoplasmic reticulum retention signal in the α
1 subunit. The endoplasmic retention brake is contained in the I–II loop in the α
1 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 α
1 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 α
1 subunit pore, so that more current passes for smaller
depolarization
In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is ess ...
s. The β subunit has effects on the kinetics of the cardiac α
1C in ''
Xenopus laevis
The African clawed frog (''Xenopus laevis'', also known as the xenopus, African clawed toad, African claw-toed frog or the ''platanna'') is a species of African aquatic frog of the family Pipidae. Its name is derived from the three short claws ...
'' 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
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
region on the α1 subunit intracellular linker between domains I and II (the Alpha Interaction Domain, AID) and a region on the GK domain of the β subunit (Alpha Interaction Domain Binding Pocket) 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 α
1 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 α
1 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 (33 kDa) 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, γ
2, γ
3, γ
4 and γ
8 are also associated with AMPA glutamate receptors.
There are 8 genes for gamma subunits:
*
γ1 (),
*
γ2 (),
*
γ3 (),
*
γ4 (),
* (),
* (),
* (), and
* ().
Muscle physiology
When a
smooth muscle cell is depolarized, it causes opening of the voltage-gated (L-type) calcium channels.
Depolarization may be brought about by stretching of the cell, agonist-binding its G protein-coupled receptor (
GPCR
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
), or
autonomic nervous system stimulation. Opening of the L-type calcium channel causes influx of extracellular Ca
2+, which then binds
calmodulin. The activated calmodulin molecule activates
myosin light-chain kinase
Myosin light-chain kinase also known as MYLK or MLCK is a serine/threonine-specific protein kinase that phosphorylates a specific myosin light chain, namely, the regulatory light chain of myosin II.
General structural features
While there ar ...
(MLCK), which phosphorylates the
myosin in
thick filaments. Phosphorylated myosin is able to form
crossbridge
The sliding filament theory explains the mechanism of muscle contraction based on muscle proteins that slide past each other to generate movement. According to the sliding filament theory, the myosin ( thick filaments) of muscle fibers slide past ...
s with
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...
thin filaments, and the smooth muscle fiber (i.e., cell) contracts via the
sliding filament mechanism
The sliding filament theory explains the mechanism of muscle contraction based on muscle proteins that slide past each other to generate movement. According to the sliding filament theory, the myosin ( thick filaments) of muscle fibers slide past ...
. (See reference
for an illustration of the signaling cascade involving L-type calcium channels in smooth muscle).
L-type calcium channels are also enriched in the
t-tubule
T-tubules (transverse tubules) are extensions of the cell membrane that penetrate into the center of skeletal and cardiac muscle cells. With membranes that contain large concentrations of ion channels, transporters, and pumps, T-tubules permi ...
s of
striated muscle
Striations means a series of ridges, furrows or linear marks, and is used in several ways:
* Glacial striation
* Striation (fatigue), in material
* Striation (geology), a ''striation'' as a result of a geological fault
* Striation Valley, in An ...
cells, i.e., skeletal and cardiac
myofiber
A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a musc ...
s. 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 (a.k.a.
ryanodine receptor, or RYR) in the
sarcoplasmic reticulum
The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are ke ...
(SR), causes opening of the RYR. In
cardiac muscle
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...
, opening of the L-type calcium channel permits influx of calcium into the cell. The calcium binds to the calcium release channels (RYRs) in the SR, opening them; this phenomenon is called "
calcium-induced calcium release
Calcium-induced calcium release (CICR) describes a biological process whereby calcium is able to activate calcium release from intracellular Ca2+ stores (e.g., endoplasmic reticulum or sarcoplasmic reticulum). Although CICR was first proposed for ...
", or CICR. However the RYRs are opened, either through mechanical-gating or CICR, Ca
2+ is released from the SR and is able to bind to
troponin C
Troponin C is a protein which is part of the troponin complex. It contains four calcium-binding EF hands, although different isoforms may have fewer than four functional calcium-binding subdomains. It is a component of thin filaments, along wi ...
on the actin filaments. The muscles then contract through the sliding filament mechanism, causing shortening of
sarcomeres
A sarcomere (Greek σάρξ ''sarx'' "flesh", μέρος ''meros'' "part") is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal muscles are composed of tubular muscle cells (called musc ...
and muscle contraction.
Changes in expression during development
Early in development, there is a high amount of expression of
T-type calcium channel
T-type calcium channels are low voltage activated calcium channels that become inactivated during cell membrane hyperpolarization but then open to depolarization. The entry of calcium into various cells has many different physiological responses a ...
s. During maturation of the nervous system, the expression of
N or
L-type currents becomes more prominent. As a result, mature neurons express more calcium channels that will only be activated when the cell is significantly
depolarized. The different expression levels of low-voltage activated (LVA) and high-voltage activated (HVA) channels can also play an important role in
neuronal differentiation. In developing
Xenopus
''Xenopus'' () (Gk., ξενος, ''xenos''=strange, πους, ''pous''=foot, commonly known as the clawed frog) is a genus of highly aquatic frogs native to sub-Saharan Africa. Twenty species are currently described within it. The two best-know ...
spinal neurons LVA calcium channels carry a spontaneous calcium transient that may be necessary for the neuron to adopt a
GABAergic phenotype as well as
process outgrowth.
Clinical significance
Voltage-gated calcium channels antibodies are associated with
Lambert-Eaton myasthenic syndrome and have also been implicated in
paraneoplastic cerebellar degeneration.
Voltage-gated calcium channels are also associated with
malignant hyperthermia
Malignant hyperthermia (MH) is a type of severe reaction that occurs in response to particular medications used during general anesthesia, among those who are susceptible. Symptoms include muscle rigidity, fever, and a fast heart rate. Complica ...
and
Timothy syndrome.
Mutations of the ''CACNA1C'' gene, with a single-nucleotide polymorphism in the third intron of the Cav1.2 gene, are associated with a variant of
long QT syndrome called
Timothy's syndrome
Timothy syndrome is a rare autosomal-dominant disorder characterized by physical malformations, as well as neurological and developmental defects, including heart QT-prolongation, heart arrhythmias, structural heart defects, syndactyly (webbing ...
and also with
Brugada syndrome.
Large-scale genetic analyses have shown the possibility that ''CACNA1C'' is associated with
bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
[
* ] and subsequently also with
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...
.
Also, a ''CACNA1C'' risk allele has been associated to a disruption in brain connectivity in patients with bipolar disorder, while not or only to a minor degree, in their unaffected relatives or healthy controls.
See also
*
Glutamate receptor
Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system ...
s
*
Inositol triphosphate receptor
*
Ion channels
*
NMDA receptors
References
External links
*
*
{{channel blockers
Electrophysiology
Membrane biology
Integral membrane proteins
Voltage-gated ion channels
Calcium channels