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Voltage-dependent calcium channels (VDCC) are a group of voltage-gated ion channels found in excitable cells (neurons, glial cells, muscle cells, etc.) with a permeability to the ion Ca2+.[1] 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. Activation of particular VDCCs allows Ca2+ entry which permits the release of neurotransmitters and hormones, muscular contraction, excitability of neurons and gene expression.

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.[2]

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 toxins. High voltage-gated calcium channels include the neural N-type channel blocked by ω-conotoxinGVIA, the R-type channel (R stands for resistant to the other blockers and toxins)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.

Current Type1,4-dihydropyridine sensitivity (DHP)ω-conotoxin sensitivity (ω-CTX)ω-agatoxin sensitivity (ω-AGA)
L-typeblocksresistantresistant
N-typeresistantblocksresistant
P/Q-typeresistantresistantblocks
R-typeresistantresistantresistant
[3]

α1 Subunit

The α1 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 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:[1]

TypeVoltageα1 subunit (gene name)Associated subunitsMost often found in
L-type calcium channel ("Long-Lasting" AKA "DHP Receptor")HVA (high voltage activated)CaV1.1 (CACNA1S)
CaV1.2 (CACNA1C)
CaV1.3 (CACNA1D)
CaV1.4 (CACNA1F)		α2δ, β, γSkeletal muscle, bone (osteoblasts)
P-type calcium channel/Q-type calcium channelHVA (high voltage activated)CaV2.1 (CACNA1A)α2δ, β, possibly γPurkinje neurons in the cerebellum / Cerebellar granule cells
N-type calcium channel ("Neural")HVA (high voltage activated)CaV2.2 (CACNA1B)α2δ/β1, β3, β4, possibly γThroughout the brain
R-type calcium channelintermediate voltage activatedCaV2.3 (CACNA1E)α2δ, β, possibly γ Cerebellar granule cells, other neurons
T-type calcium channel ("Transient")low voltage activatedCaV3.1 (CACNA1G)
CaV3.2 (CACNA1H)
CaV3.3 (CACNA1I)		neurons, cells that have pacemaker activity, bone (osteocytes)

α2δ Subunit

The α2δ gene forms two subunits α2 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 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 (Neurontin®) and pregabalin (Lyrica®), that also find use in treating chronic neuropathic pain.

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 α1 subunit I-II cytoplasmic loop and regulates HVGCC activity. There are four known isoforms of the β subunit: CACNB1, CACNB2, CACNB3, and 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.[5] 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 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 (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 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 (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, γ2, γ3, γ4 and γ8 are also associated with AMPA glutamate receptors.

There are 8 genes for gamma subunits: CACNG1, CACNG2, CACNG3, CACNG4, CACNG5, CACNG6, CACNG7, and CACNG8.

References

1. ^ Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J (2005). "International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels". Pharmacol Rev 57 (4): 411-25. DOI:10.1124/pr.57.4.5. PMID 16382099. 
2. ^ Dolphin AC (2006). "A short history of voltage-gated calcium channels". Br J Pharmacol 147 (Suppl 1): S56-62. DOI:10.1038/sj.bjp.0706442. PMID 16402121. 
3. ^ Dunlap K, Luebke JI, Turner TJ (2005). "Exocytotic Ca2+ channels in mammalian central neurons". Trends Neurosci. 18: 89-98. PMID 7537420. 
4. ^ Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J (2005). "International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels". Pharmacol Rev 57 (4): 411-25. DOI:10.1124/pr.57.4.5. PMID 16382099. 
5. ^ Bichet D, Cornet V, Geib S, Carlier E, Volsen S, Hoshi T, Mori Y, De Waard M (2000). "The I-II loop of the Ca2+ channel α1 subunit contains an endoplasmic reticulum retention signal antagonized by the beta subunit.". Neuron 25 (1): 177-90. DOI:10.1016/S0896-6273(00)80881-8. PMID 10707982. 

See also

External links

 •  • [ e]
Membrane transport protein: ion channels
Ca2+: Calcium channelVoltage-dependent calcium channel (L-type/CACNA1C, N-type, P-type, Q-type, R-type, T-type) - Inositol triphosphate receptor - Ryanodine receptor - Cation channels of sperm
Na+: Sodium channelNav1.4 - Nav1.5 - Nav1.7 - Epithelial sodium channel
K+: Potassium channelVoltage-gated (KvLQT1, KvLQT2, KvLQT3, HERG, Shaker gene, KCNE1) - Calcium-activated (BK channel, SK channel, SK3) - Inward-rectifier (ROMK, KCNJ2, KCNJ11) - Tandem pore domain
Cl-: Chloride channelCystic fibrosis transmembrane conductance regulator
PorinAquaporin (1, 2, 3, 4) - Voltage-dependent anion channel
Cations: TRPTRPA - TRPC (TRPC6) - TRPM (TRPM6) - TRPML (Mucolipin-1) - TRPP - TRPV (TRPV1, TRPV6)
Other/generalGap junction - Stretch-activated ion channel - Ligand-gated ion channel - Voltage-gated ion channel - Cyclic nucleotide-gated ion channel - Two-pore channel
Voltage-gated ion channels are a class of transmembrane ion channels that are activated by changes in electrical potential difference near the channel; these types of ion channels are especially critical in neurons, but are common in many types of cells.
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Ion channels are pore-forming proteins that help to establish and control the small voltage gradient across the plasma membrane of all living cells (see cell potential) by allowing the flow of ions down their electrochemical gradient.
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Neurons (also known as neurones and nerve cells) are electrically excitable cells in the nervous system that process and transmit information. In vertebrate animals, neurons are the core components of the brain, spinal cord and peripheral nerves.
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Glial cells, commonly called neuroglia or simply glia (greek for "glue"), are non-neuronal cells that provide support and nutrition, maintain homeostasis, form myelin, and participate in signal transmission in the nervous system.
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In electromagnetism, permeability is the degree of magnetization of a material that responds linearly to an applied magnetic field. Magnetic permeability is represented by the Greek letter μ. The term was coined in September, 1885 by Oliver Heaviside.
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Calcium (IPA: /ˈkalsiəm/) is the chemical element in the periodic table that has the symbol Ca and atomic number 20. It has an atomic mass of 40.078.
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Physiology (from Greek: φυσις, physis, “nature, origin”; and λόγος, logos, "knowledge") is the study of the mechanical, physical, and biochemical functions of living organisms.
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Membrane potential (or transmembrane potential or transmembrane potential difference or transmembrane potential gradient), is the electrical potential difference (voltage) across a cell's plasma membrane.
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In biology, depolarization is a decrease in the absolute value of a cell's membrane potential. Thus, changes in membrane voltage in which the membrane potential becomes less positive or less negative are both depolarizations.
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Membrane potential (or transmembrane potential or transmembrane potential difference or transmembrane potential gradient), is the electrical potential difference (voltage) across a cell's plasma membrane.
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An epithet (Greek — επιθετον and Latin — epitheton; literally meaning 'imposed') is a descriptive word or phrase that has become a fixed formula.
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Calcium (IPA: /ˈkalsiəm/) is the chemical element in the periodic table that has the symbol Ca and atomic number 20. It has an atomic mass of 40.078.
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Neurotransmitters are chemicals that are used to relay, amplify and modulate signals between a neuron and another cell. According to the prevailing beliefs of the 1960s, a chemical can be classified as a neurotransmitter if it meets the following conditions:

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hormone (from Greek όρμή - "to set in motion") is a chemical messenger that carries a signal from one cell (or group of cells) to another. All multicellular organisms produce hormones (including plants - see phytohormone).
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MUSCLE (multiple sequence comparison by log-expectation) is public domain, multiple sequence alignment software for protein and nucleotide sequences.
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For vocabulary, see Glossary of gene expression terms


Gene expression is the process by which the inheritable information in a gene, such as the DNA sequence, is made into a functional gene product, such as protein or RNA.
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toxin (Greek: τοξικόν, toxikon, lit. (poison) for use on arrows) is a poisonous substance produced by living cells or organisms.
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Neurons (also known as neurones and nerve cells) are electrically excitable cells in the nervous system that process and transmit information. In vertebrate animals, neurons are the core components of the brain, spinal cord and peripheral nerves.
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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.
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In animals, the brain or encephalon (Greek for "in the skull"), is the control center of the central nervous system, responsible for behavior. The brain is located in the head, protected by the skull and close to the primary sensory apparatus of vision, hearing,
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Skeletal muscle is a type of striated muscle, usually attached to the skeleton. Skeletal muscles are used to create movement, by applying force to bones and joints; via contraction.
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Smooth muscle is a type of non-striated muscle, found within the "walls" of hollow organs and elsewhere like the bladder and abdominal cavity, the uterus, male and female reproductive tracts, the gastrointestinal tract, the respiratory tract, the vasculature, the skin and the
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'Cardiac muscle' is a type of involuntary striated muscle found within the heart. Its function is to "pump" blood through the circulatory system by contracting.
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Dihydropyridine is a molecule based upon pyridine, and the parent of a class of molecules that have been semi-saturated with two substituents replacing one double bond. They are particularly well known in pharmacology as L-type calcium channel blockers.
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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.
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The L-type calcium channel is a type of voltage-dependent calcium channel. Like the others of this class, the α1 subunit is the one that determines most of the channel's properties.
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The p-type calcium channel is a type of voltage-dependent calcium channel. Like the others of this class, the α1 subunit is the one that determines most of the channel's properties.
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The Q-type calcium channel is a type of voltage-dependent calcium channel. Like the others of this class, the α1 subunit is the one that determines most of the channel's properties.
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The cerebellum (Latin: "little brain") is a region of the brain that plays an important role in the integration of sensory perception and motor output. Many neural pathways link the cerebellum with the motor cortex—which sends information to the muscles causing them
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granule cells refer to tiny neurons (a type of cell) that are around 10 micrometres in diameter. Granule cells are found within the granular layer of the cerebellum, layer 4 of cerebral cortex, the dentate gyrus of the hippocampus, and in the olfactory bulb.
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