Voltage - dependent calcium channel - wikipedia Voltage - dependent calcium channel Voltage - dependent calcium channels ( VDCCs ) 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 Ca. These channels are slightly permeable to sodium ions, so they are also called Ca - 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 ( i.e., opened ) at depolarized membrane potentials and this is the source of the `` voltage - dependent '' epithet. The concentration of calcium ( Ca ions ) is normally several thousand times higher outside of the cell than inside. Activation of particular VDCCs allows Ca 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 ( APA ), 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. Contents 1 Structure 2 Channel subunits 2.1 α Subunit 2.2 α δ Subunit 2.3 β Subunit 2.4 γ Subunit 2.5 Muscle physiology 2.6 Changes in expression during development 3 See also 4 References 5 External links Structure Voltage - dependent calcium channels are formed as a complex of several different subunits : α, α δ, β, and γ. The α 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 toxins. High - voltage - gated calcium channels include the neural N - type channel blocked by ω - conotoxin GVIA, 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 Α subunit The α 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 subunit forms the Ca selective pore, which contains voltage - sensing machinery and the drug / toxin - binding sites. A total of ten α subunits that have been identified in humans : α 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. 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 ). VDCCs are subject to rapid inactivation, which is thought to consist of 2 components : voltage - dependent ( VDI ) and calcium - dependent ( CDI ). These are distinguished by using either Ba or Ca as the charge carrier in the external recording solution ( in vitro ). The CDI component is attributed to the binding of the Ca - binding signaling protein calmodulin ( CaM ) to at least 1 site on the channel, as Ca - 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 α subunit ( gene name ) Associated subunits Most often found in L - type calcium channel ( `` Long - Lasting '' AKA `` DHP Receptor '' ) HVA ( high voltage activated ) Ca 1.1 ( CACNA1S ) Ca 1.2 ( CACNA1C ) Ca 1.3 ( CACNA1D ) Ca 1.4 ( CACNA1F ) α δ, 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 2.1 ( CACNA1A ) α δ, β, possibly γ Purkinje neurons in the cerebellum / Cerebellar granule cells N - type calcium channel ( `` Neural '' / `` Non-L '' ) HVA ( high voltage activated ) Ca 2.2 ( CACNA1B ) α δ / β, β, β, possibly γ Throughout the brain and peripheral nervous system. R - type calcium channel ( `` Residual '' ) intermediate voltage activated Ca 2.3 ( CACNA1E ) α δ, β, possibly γ Cerebellar granule cells, other neurons T - type calcium channel ( `` Transient '' ) low voltage activated Ca 3.1 ( CACNA1G ) Ca 3.2 ( CACNA1H ) Ca 3.3 ( CACNA1I ) neurons, cells that have pacemaker activity, bone ( osteocytes ) Α δ subunit The α δ gene forms two subunits : α 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 is the extracellular glycosylated subunit that interacts the most with the α 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 δ genes : CACNA2D1 ( CACNA2D1 ), CACNA2D2 ( CACNA2D2 ), ( CACNA2D3 ), ( CACNA2D4 ). Co-expression of the α δ enhances the level of expression of the α 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 δ - 1 and α δ - 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 α δ 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 ( 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 subunit I - II cytoplasmic loop and regulates HVGCC activity. There are four known genes for 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 α subunit conformation and delivering it to the cell membrane by its ability to mask an endoplasmic reticulum retention signal in the α subunit. The endoplasmic retention brake is contained in the I -- II loop in the α 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 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 subunit pore, so that more current passes for smaller depolarizations. The β subunit has effects on the kinetics of the cardiac α C 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 α 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 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, γ, γ and γ 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. 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 Ca, 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 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, Ca 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. Changes in expression during development Early in development, there is a high amount of expression of T - type calcium channels. 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 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. See also Glutamate receptors Inositol triphosphate receptor Ion channels NMDA receptors Ryanodine receptor Voltage - gated ion channels Gabapentin Pregabalin References ^ Jump up to : 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. PMID 16382099. doi : 10.1124 / pr. 57.4. 5. Jump up ^ 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. PMID 11823393. doi : 10.1007 / BF03020488. Jump up ^ 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. Jump up ^ Michael P. Walsh ; et all. `` Thromboxane A2 - induced contraction of rat caudal arterial smooth muscle involves activation of Ca entry and Ca sensitization : Rho - associated kinase - mediated phosphorylation of MYPT1 at Thr - 855 but not Thr - 697 '' ( PDF ). Archived from the original ( PDF ) on July 13, 2011. Jump up ^ 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. PMID 25151951. doi : 10.1016 / j. jsbmb. 2014.08. 012. Jump up ^ Dolphin AC ( 2006 ). `` A short history of voltage - gated calcium channels ''. Br J Pharmacol. 147 ( Suppl 1 ) : S56 -- 62. PMC 1760727. PMID 16402121. doi : 10.1038 / sj. bjp. 0706442. 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PMID 16038964. doi : 10.1016 / j. pbiomolbio. 2005.05. 013. Jump up ^ 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. ISSN 0091 - 3057. PMID 26234470. doi : 10.1016 / j. pbb. 2015.07. 014. Jump up ^ Bichet D, Cornet V, Geib S, Carlier E, Volsen S, Hoshi T, Mori Y, De Waard M ( 2000 ). `` The I -- II loop of the Ca channel α subunit contains an endoplasmic reticulum retention signal antagonized by the beta subunit ''. Neuron. 25 ( 1 ) : 177 -- 90. PMID 10707982. doi : 10.1016 / S0896 - 6273 ( 00 ) 80881 - 8. ^ Jump up to : Webb RC ( 2003 ). `` Smooth muscle contraction and relaxation ''. Adv Physiol Educ. 27 ( 1 -- 4 ) : 201 -- 6. PMID 14627618. doi : 10.1152 / advan. 00025.2003. Jump up ^ 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. Jump up ^ Sanes, Dan H. ; Reh, Thomas A ( 2012 ). Development of the nervous system ( Third ed. ). Elsevier Academic Press. pp. 211 -- 214. ISBN 9780080923208. OCLC 762720374. Jump up ^ Rosenberg, Sheila S. ; Spitzer, Nicholas C. ( 2017 - 03 - 10 ). `` Calcium Signaling in Neuronal Development ''. Cold Spring Harbor Perspectives in Biology. 3 ( 10 ). ISSN 1943 - 0264. PMC 3179332. PMID 21730044. doi : 10.1101 / cshperspect. a004259. 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 ) Membrane transport protein : ion channels ( TC 1A ) Ca : Calcium channel Ligand - gated Inositol trisphosphate receptor Ryanodine receptor Voltage - gated L - type / Ca α 1.1 1.2 1.3 1.4 N - type / Ca α2. 2 P - type / Ca α 2.1 Q - type / Ca α2. 1 R - type / Ca α2. 3 T - type / Ca α 3.1 3.2 3.3 α δ - subunits β - subunits β1 β2 β3 β4 γ - subunits γ1 γ2 γ3 γ4 Cation channels of sperm Two - pore channel Na : Sodium channel Constitutively active Epithelial sodium channel α β γ δ Proton - gated Amiloride - sensitive cation channel Voltage - gated Na α 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 7A Na β K : Potassium channel Calcium - activated BK channel α1 β1 β2 β3 β4 SK channel SK1 SK2 SK3 IK channel IK1 1.1 2.1 2.2 2.3 3.1 4.1 4.2 5.1 Inward - rectifier 1.1 2.1 2.2 2.3 2.4 2.6 GIRK / K 3.1 3.2 3.3 3.4 4.1 4.2 5.1 6.1 6.2 7.1 Tandem pore domain K2P 5 6 7 9 10 12 13 15 16 17 18 Voltage - gated K α1 - 6 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 2.1 2.2 3.1 3.2 3.3 3.4 4.1 4.2 4.3 5.1 6.1 6.2 6.3 6.4 K α7 - 12 7.1 7.2 7.3 7.4 7.5 8.1 8.2 9.1 9.2 9.3 10.1 10.2 11.1 / hERG 11.2 11.3 12.1 12.2 12.3 K β KCNIP minK / ISK minK / ISK - like MiRP Shaker gene Miscellaneous Cl : Chloride channel Calcium - activated chloride channels Anoctamin ANO1 Bestrophin Chloride Channel Accessory CFTR CLCN 5 6 7 KA KB CLIC 5 6 L1 CLNS 1A 1B H : Proton channel HVCN1 M : CNG cation channel α β HCN FC M : TRP cation channel TRPA ( 1 ) TRPC 4AP 5 6 7 TRPM 5 6 7 8 TRPML TRPN TRPP TRPV 5 6 H O ( + solutes ) : Porin Aquaporin 0 5 6 7 8 9 Voltage - dependent anion channel General bacterial porin family Cytoplasm : Gap junction Connexin GJA1 GJA3 GJA4 GJA5 GJA8 GJA9 GJA10 GJB1 GJB2 GJB3 GJB4 GJB5 GJB6 GJB7 GJC1 GJC2 GJC3 GJD2 GJD3 GJD4 Innexin By gating mechanism Ion channel class Ligand - gated Light - gated Voltage - gated Stretch - activated see also disorders Retrieved from `` https://en.wikipedia.org/w/index.php?title=Voltage-dependent_calcium_channel&oldid=802233728 '' Categories : Electrophysiology Membrane biology Integral membrane proteins Voltage - gated ion channels Calcium channels Talk Contents About Wikipedia 한국어 Português Slovenščina Српски / srpski Srpskohrvatski / српскохрватски Edit links This page was last edited on 24 September 2017, at 21 : 03. 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Question: where are the calcium-voltage gated channels located in the neuron
Answer: membrane