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Voltage-dependent calcium channels (VDCC) are a group of voltage-gated ion channels found in the membrane of excitable cells (e.g., muscle, glial cells, neurons, etc.) with a permeability to the calcium ion Ca²⁺.^[1]^[2] 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.^[3] At physiologic or resting membrane potential, VDCCs are normally closed. They are activated (i.e., opened) at depolarized membrane potentials and this is the source of the "voltage-dependent" epithet. The concentration of calcium (Ca²⁺ ions) 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,^[4] 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 (APA), and in the latter T-type VDCCs correlated with plasma aldosterone levels of patients.^[5] 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, β_1-4, and γ. The α₁ subunit forms the ion conducting pore while the associated subunits have several functions including modulation of gating.^[6]

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, except SNX-482) 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 Type	1,4-dihydropyridine sensitivity (DHP)	ω-conotoxin sensitivity (ω-CTX)	ω-agatoxin sensitivity (ω-AGA)
L-type	blocks	resistant	resistant
N-type	resistant	blocks	resistant
P/Q-type	resistant	resistant	blocks
R-type	resistant	resistant	resistant

^[7]

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] α₁ 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 evolutionary related to VDCCs.^[8] 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).^[9] VDCCs are subject to rapid inactivation, which is thought to consist of 2 components: voltage-dependent (VDI) and calcium-dependent (CDI).^[10] These are distinguished by using either Ba²⁺ or Ca²⁺ as the charge carrier in the external recording solution (in vitro). The CDI component is attributed to the binding of the Ca²⁺-binding signaling protein calmodulin (CaM) 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.

Type	Voltage	α₁ subunit (gene name)	Associated subunits	Most often found in
L-type calcium channel ("Long-Lasting" AKA "DHP Receptor")	HVA (high voltage activated)	Ca_v1.1 (CACNA1S) Ca_v1.2 (CACNA1C) Ca_v1.3 (CACNA1D) Ca_v1.4 (CACNA1F)	α₂δ, β, γ	Skeletal muscle, smooth muscle, bone (osteoblasts), ventricular myocytes** (responsible for prolonged action potential in cardiac cell; also termed DHP receptors), dendrites and dendritic spines of cortical neurones
P-type calcium channel ("Purkinje") /Q-type calcium channel	HVA (high voltage activated)	Ca_v2.1 (CACNA1A)	α₂δ, β, possibly γ	Purkinje neurons in the cerebellum / Cerebellar granule cells
N-type calcium channel ("Neural"/"Non-L")	HVA (high-voltage-activated)	Ca_v2.2 (CACNA1B)	α₂δ/β₁, β₃, β₄, possibly γ	Throughout the brain and peripheral nervous system.
R-type calcium channel ("Residual")	intermediate-voltage-activated	Ca_v2.3 (CACNA1E)	α₂δ, β, possibly γ	Cerebellar granule cells, other neurons
T-type calcium channel ("Transient")	low-voltage-activated	Ca_v3.1 (CACNA1G) Ca_v3.2 (CACNA1H) Ca_v3.3 (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 (CACNA2D1),
CACNA2D2 (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. The α₂δ subunit is also a binding site of the central depressant and anxiolytic drug phenibut, in addition to actions at other targets.^[11]

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 (CACNB1),
CACNB2 (CACNB2),
CACNB3 (CACNB3),
CACNB4 (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.^[12] 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 (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:

γ1 (CACNG1),
γ2 (CACNG2),
γ3 (CACNG3),
γ4 (CACNG4),
(CACNG5),
(CACNG6),
(CACNG7), and
(CACNG8).

Muscle Physiology

When a smooth muscle cell is depolarized, it causes opening of the voltage-gated (L-type) calcium channels.^[13]^[14] Depolarization may be brought about by stretching of the cell, agonist-binding its G protein-coupled receptor (GPCR), 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 (MLCK), which phosphorylates the myosin in thick filaments. Phosphorylated myosin is able to form crossbridges with actin thin filaments, and the smooth muscle fiber (i.e., cell) contracts via the sliding filament mechanism. (See reference^[13] 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-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 (a.k.a. ryanodine receptor, or RYR) in the sarcoplasmic reticulum (SR), 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 (RYRs) 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.

References

^ ^a ^b 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.
^ Yamakage M, Namiki A (2002). "Calcium channels — basic aspects of their structure, function and gene encoding; anesthetic action on the channels — a review" (PDF). Can J Anaesth 49 (2): 151–64. doi:10.1007/BF03020488. PMID 11823393.
^ Hall, John E. (2011). Guyton and Hall Textbook of Medical Physiology with Student Consult Online Access (PDF) (12th ed.). Philadelphia: Elsevier Saunders. p. 64. ISBN 978-1-4160-4574-8. Retrieved 2011-03-22.
^ Michael P. Walsh, et all. "Thromboxane A2-induced contraction of rat caudal arterial smooth muscle involves activation of Ca²⁺ entry and Ca²⁺ sensitization: Rho-associated kinase-mediated phosphorylation of MYPT1 at Thr-855 but not Thr-697" (PDF). ^{[dead link]}
^ Saulo J.A. Felizola, Takashi Maekawa, Yasuhiro Nakamura, Fumitoshi Satoh, Yoshikiyo Ono, Kumi Kikuchi, Shizuka Aritomi, Keiichi Ikeda, Michihiro Yoshimura, Katsuyoshi Tojo, Hironobu Sasano. (2014). "Voltage-gated calcium channels in the human adrenal and primary aldosteronism.". J Steroid Biochem Mol Biol. 144 (part B): 410–416. doi:10.1016/j.jsbmb.2014.08.012. PMID 25151951.
^ 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. PMC 1760727. PMID 16402121.
^ Dunlap K, Luebke JI, Turner TJ (1995). "Exocytotic Ca²⁺ channels in mammalian central neurons". Trends Neurosci. 18 (2): 89–98. doi:10.1016/0166-2236(95)93882-X. PMID 7537420.
^ Zakon, H. H. (2012). "Adaptive evolution of voltage-gated sodium channels: The first 800 million years". Proceedings of the National Academy of Sciences 109: 10619–10625. doi:10.1073/pnas.1201884109. PMC 3386883. PMID 22723361.
^ Tombola, Francesco; Pathak, Medha M.; Isacoff, Ehud Y. (1 November 2006). "How Does Voltage Open an Ion Channel?". Annual Review of Cell and Developmental Biology 22 (1): 23–52. doi:10.1146/annurev.cellbio.21.020404.145837.
^ Cens, T; Rousset, M; Leyris, JP; Fesquet, P; Charnet, P (Jan–Apr 2006). "Voltage- and calcium-dependent inactivation in high voltage-gated Ca²⁺ channels". Progress in biophysics and molecular biology 90 (1–3): 104–17. doi:10.1016/j.pbiomolbio.2005.05.013. PMID 16038964.
^ Zvejniece, Liga; Vavers, Edijs; Svalbe, Baiba; Veinberg, Grigory; Rizhanova, Kristina; Liepins, Vilnis; Kalvinsh, Ivars; Dambrova, Maija (2015). "R-phenibut binds to the α2–δ subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects". Pharmacology Biochemistry and Behavior 137: 23–29. doi:10.1016/j.pbb.2015.07.014. ISSN 0091-3057.
^ 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.
^ ^a ^b Webb RC (2003). "Smooth muscle contraction and relaxation". Adv Physiol Educ 27 (1–4): 201–6. doi:10.1152/advan.00025.2003. PMID 14627618.
^ Alberts, Bruce; Johnson A; Lewis J; Raff M; Roberts K; Walter P (2002). Molecular Biology of the Cell (4th ed.). New York, NY: Garland Science. p. 1616 pp. ISBN 0-8153-3218-1.

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 (MeSH)

English Journal

UTP - Gated Signaling Pathways of 5-HT Release from BON Cells as a Model of Human Enterochromaffin Cells.

Liñán-Rico A1, Ochoa-Cortes F1, Zuleta-Alarcon A1, Alhaj M1, Tili E1,2, Enneking J1, Harzman A3, Grants I1, Bergese S1, Christofi FL1.
Frontiers in pharmacology.Front Pharmacol.2017 Jul 13;8:429. doi: 10.3389/fphar.2017.00429. eCollection 2017.
PMID 28751862

Role of renal vascular potassium channels in physiology and pathophysiology.

Salomonsson M1, Brasen JC2, Sorensen CM3.
Acta physiologica (Oxford, England).Acta Physiol (Oxf).2017 Sep;221(1):14-31. doi: 10.1111/apha.12882. Epub 2017 Apr 25.
PMID 28371470

Antihypertensive effects of androgens in conscious, spontaneously hypertensive rats.

Perusquía M1, Herrera N2, Ferrer M3, Stallone JN4.
The Journal of steroid biochemistry and molecular biology.J Steroid Biochem Mol Biol.2017 Mar;167:106-114. doi: 10.1016/j.jsbmb.2016.11.016. Epub 2016 Nov 23.
PMID 27888135

Japanese Journal

冷却フィンを用いた除去液噴霧による排気ガス中揮発性有機塩素化合物(VOCC)の循環効率的な除去処理技術 (特集新世代環境エネルギー技術の創製)

ケミカルエンジニヤリング = Chemical engineering 60(7), 485-489, 2015-07
NAID 40020519848

空気流動真空蒸発法によるVOCC(Volatile Organochlorine Compounds)ガスを吸収した廃溶剤再生装置の開発

廃棄物資源循環学会研究発表会講演集 24(0), 651, 2013
NAID 130005470893

新しい遮断薬を用いたエンドセリンの血管収縮に関与するCa<SUP>2+</SUP>流入チャンネルの検討

日本薬理学雑誌 114(supplement), 103-109, 1999
NAID 130000754526

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BRA 18 EGAM/VOCC Etiquette Bio VOCC VOCC for – Computer

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リンク元	「電位依存性カルシウムチャネル」「電位作動型カルシウムチャネル」

「電位依存性カルシウムチャネル」

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英: voltage-dependent calcium channel, VDCC
同: 電位関門型カルシウムチャネル voltage-gated calcium channel VGCC、電位作動型カルシウムチャネル voltage-operated calcium channel VOCC, 電位依存性Ca²⁺チャネル
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