View source for Voltage-dependent calcium channel

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==Overview==

'''Voltage-dependent calcium channels''' (VDCC) are a group of [[voltage-gated ion channel|voltage-gated]] [[ion channel]]s found in excitable cells  (''e.g.'', muscle, [[glial cell]]s, [[neuron]]s, etc.) with a [[Permeability (electromagnetism)|permeability]] to the ion [[calcium|Ca<sup>2+</sup>]].<ref name="Catterall">{{cite journal |author=Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J|title=International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels|journal= Pharmacol Rev |volume= 57 |issue= 4 |pages= 411-25 |year= 2005|doi = 10.1124/pr.57.4.5 |pmid= 16382099}}</ref><ref name="pmid11823393">{{cite journal | author = Yamakage M, Namiki A | title = Calcium channels--basic aspects of their structure, function and gene encoding; anesthetic action on the channels--a review | journal = Can J Anaesth | volume = 49 | issue = 2 | pages = 151–64 | year = 2002 | pmid = 11823393 | doi = | issn = | url = http://www.cja-jca.org/cgi/content/abstract/49/2/151 }}</ref>  At [[physiologic]] or resting [[membrane potential]], VDCCs are normally closed. They are activated (''i.e.'', opened) at [[depolarization|depolarized]] [[membrane potential]]s and this is the source of the "voltage-dependent" [[epithet]].  Activation of particular VDCCs allows [[calcium|Ca<sup>2+</sup>]] entry into the cell, which depending on the cell type, results in [[muscle|muscular contraction]], excitation of neurons, up-regulation of [[gene expression]], or release of [[hormone]]s or [[neurotransmitter]]s.

==Structure==
Voltage-dependent calcium channels are formed as a complex of several different subunits: α<sub>1</sub>, α<sub>2</sub>δ, β<sub>1-4</sub>, and γ. The α<sub>1</sub> subunit forms the ion conducting pore while the associated subunits have several functions including modulation of gating.<ref name="Dolphin">{{cite journal |author=Dolphin AC|title=A short history of voltage-gated calcium channels|journal= Br J Pharmacol |volume= 147 |issue= Suppl 1 |pages= S56-62 |year= 2006 |doi = 10.1038/sj.bjp.0706442 |pmid= 16402121}}</ref>

==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]]s. High-voltage-gated calcium channels include the [[neuron|neural]] N-type channel blocked by ω-[[conotoxin]]GVIA, the R-type channel (R stands for '''R'''esistant 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 muscle|skeletal]], [[smooth muscle|smooth]], and [[cardiac muscle]] and for hormone secretion in endocrine cells.

{| class="wikitable"  | style="text-align:center"
| '''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
|}<ref name="Dunlap">{{cite journal |author=Dunlap K, Luebke JI, Turner TJ|title=Exocytotic Ca<sup>2+</sup> channels in mammalian central neurons|journal= Trends Neurosci. |volume= 18 |issue = |pages= 89-98 |year= 2005 |doi = |pmid= 7537420}}</ref>

===α<sub>1</sub> Subunit===
The α<sub>1</sub> 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<sub>1</sub> subunit forms the Ca<sup>2+</sup> selective pore, which contains voltage-sensing machinery and the drug/toxin-binding sites. A total of ten α<sub>1</sub> subunits that have been identified in humans:<ref name="Catterall">{{cite journal |author=Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J|title=International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels|journal= Pharmacol Rev |volume= 57 |issue= 4 |pages= 411-25 |year= 2005|doi = 10.1124/pr.57.4.5 |pmid= 16382099}}</ref>

{| class="wikitable"  | style="text-align:center"
| '''Type''' || '''Voltage''' || '''α<sub>1</sub> subunit (gene name)''' || '''Associated subunits''' || '''Most often found in''' 
 |- 
 | [[L-type calcium channel]] ("Long-Lasting" AKA "DHP Receptor")|| HVA (high voltage activated)|| [[Cav1.1|Ca<sub>v</sub>1.1]] ({{Gene|CACNA1S}})<br /> [[Cav1.2|Ca<sub>v</sub>1.2]] ({{Gene|CACNA1C}})<br /> [[Cav1.3|Ca<sub>v</sub>1.3]] ({{Gene|CACNA1D}})<br /> [[Cav1.4|Ca<sub>v</sub>1.4]] ({{Gene|CACNA1F}}) || α<sub>2</sub>δ, β, γ || Skeletal 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) || [[Cav2.1|Ca<sub>v</sub>2.1]] ({{Gene|CACNA1A}}) || α<sub>2</sub>δ, β, possibly γ || [[Purkinje neurons]] in the cerebellum / [[Cerebellum| Cerebellar]] [[granule cell]]s
 |- 
 | [[N-type calcium channel]] ("Neural") || HVA (high-voltage-activated) || Ca<sub>v</sub>2.2 ({{Gene|CACNA1B}}) || α<sub>2</sub>δ/β<sub>1</sub>, β<sub>3</sub>, β<sub>4</sub>, possibly γ || Throughout the [[brain]]
 |- 
 | [[R-type calcium channel]] ("Residual") || intermediate-voltage-activated || Ca<sub>v</sub>2.3 ({{Gene|CACNA1E}}) || α<sub>2</sub>δ, β, possibly γ || [[Cerebellum| Cerebellar]] [[granule cell]]s, other neurons
 |- 
 | [[T-type calcium channel]] ("Transient") || low-voltage-activated || Ca<sub>v</sub>3.1 ({{Gene|CACNA1G}})<br /> [[CACNA1H|Ca<sub>V</sub>3.2]] ({{Gene|CACNA1H}})<br /> Ca<sub>V</sub>3.3 ({{Gene|CACNA1I}}) || || neurons, cells that have pacemaker activity, bone (osteocytes) 
|}

===α<sub>2</sub>δ Subunit===
The α<sub>2</sub>δ gene forms two subunits α<sub>2</sub> 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<sub>2</sub> is the extracellular glycosylated subunit that interacts the most with the α<sub>1</sub> 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<sub>2</sub>δ genes: 
* [[CACNA2D1]] ({{Gene|CACNA2D1}}),
* ({{Gene|CACNA2D2}}),
* ({{Gene|CACNA2D3}}),
* ({{Gene|CACNA2D4}}).

Co-expression of the α<sub>2</sub>δ enhances the level of expression of the α<sub>1</sub> 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<sub>2</sub>δ-1 and α<sub>2</sub>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.

===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<sub>1</sub> subunit I-II cytoplasmic loop and regulates HVGCC activity. There are four known isoforms of the β subunit:
* [[CACNB1]] ({{Gene|CACNB1}}),
* [[CACNB2]] ({{Gene|CACNB2}}),
* [[CACNB3]] ({{Gene|CACNB3}}),
* [[CACNB4]] ({{Gene|CACNB4}}).

It is hypothesized that the cytosolic β subunit has a major role in stabilizing the final α<sub>1</sub> subunit conformation and delivering it to the cell membrane by its ability to mask an [[endoplasmic reticulum]] retention signal in the α<sub>1</sub> subunit. The endoplasmic retention brake is contained in the I-II loop in the α<sub>1</sub> subunit that becomes masked when the β subunit binds.<ref>{{cite journal | author = Bichet D, Cornet V, Geib S, Carlier E, Volsen S, Hoshi T, Mori Y, De Waard M | title = The I-II loop of the Ca<sup>2+</sup> channel α<sub>1</sub> subunit contains an endoplasmic reticulum retention signal antagonized by the beta subunit. | journal = Neuron | volume = 25 | issue = 1 | pages = 177-90 | year = 2000 |doi = 10.1016/S0896-6273(00)80881-8 | id = PMID 10707982}}</ref>  Therefore the β subunit functions initially to regulate the current density by controlling the amount of α<sub>1</sub> 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<sub>1</sub> subunit pore, so that more current passes for smaller [[depolarization]]s. The β subunit has effects on the kinetics of the cardiac α<sub>1</sub>C 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 α<sub>1</sub> 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<sub>1</sub> 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<sub>2</sub>, γ<sub>3</sub>, γ<sub>4</sub> and γ<sub>8</sub> are also associated with AMPA glutamate receptors.

There are 8 genes for gamma subunits:
* [[CACNG1|γ1]] ({{Gene|CACNG1}}),
* [[CACNG2|γ2]] ({{Gene|CACNG2}}),
* [[CACNG3|γ3]] ({{Gene|CACNG3}}),
* [[CACNG4|γ4]] ({{Gene|CACNG4}}),
* ({{Gene|CACNG5}}),
* ({{Gene|CACNG6}}),
* ({{Gene|CACNG7}}), and
* ({{Gene|CACNG8}}).

===Muscle Physiology===

When a [[smooth muscle]] cell is depolarized, it causes opening of the voltage-gated, or L-type, calcium channels.<ref name="pmid14627618">{{cite journal | author = Webb RC | title = Smooth muscle contraction and relaxation | journal = Adv Physiol Educ | volume = 27 | issue = 1-4 | pages = 201–6 | year = 2003 | pmid = 14627618 | doi = 10.1152/advan.00025.2003 | issn = | url = http://advan.physiology.org/cgi/content/full/27/4/201 }}</ref><ref name="MBC">{{cite book | last= Alberts | first= Bruce | authorlink= | coauthors= Johnson A, Lewis J, Raff M, Roberts K, Walter P | editor= | others= | title= Molecular Biology of the Cell |edition= 4<sup>th</sup> Edition | year= 2002 | publisher= Garland Science | location= New York, NY |language= |isbn= 0-8153-3218-1 |oclc= |doi= |id= |pages= 1616 pp }}</ref>  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 infux of extracellular Ca<sup>2+</sup>, which then binds [[calmodulin]].  The activated calmodulin molecule activates [[myosin light-chain kinase]] (MLCK), which phosphorylates the [[myosin]] in [[thick filament]]s.  Phosphorylated myosin is able to form [[crossbridge]]s with [[actin]] [[thin filament]]s, and the smooth muscle fiber (i.e., cell) contracts via the [[sliding filament mechanism]].  (See reference<ref name="pmid14627618"/> 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]]s of [[striated muscle]] cells, i.e., skeletal and cardiac [[myofiber]]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]] (SR), causes opening of the RYR.  In [[cardiac muscle]], opening of the L-type caclium 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<sup>2+</sup> 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==
{{Reflist|2}}

==See also==
* [[Glutamate receptor]]s
* [[Inositol triphosphate receptor]]
* [[Ion channel]]s
* [[NMDA receptor]]s
* [[Ryanodine receptor]]
* [[Voltage-gated ion channel]]s

==External links==
* [http://www.iuphar-db.org/iuphar-ic/index.html IUPHAR - International Union of Pharmacology: Voltage gated ion channel Compendium ]
* {{MeshName|Calcium+Channels}}

{{Ion channels}}

[[Category:Ion channels]]
[[Category:Membrane biology]]
[[Category:Integral membrane proteins]]

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