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'''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 = 10.1007/BF03020488| issn = | url = http://www.springerlink.com/content/n21476v8k20w3l46/fulltext.pdf}}</ref> These channels are slightly permeable to [[sodium ion]]s, so they are also called Ca<sup>2+</sup>-Na<sup>+</sup> channels, but their permeability to calcium is about 1000-fold greater than to sodium under normal physiological conditions.<ref>{{cite book |title=Guyton and Hall Textbook of Medical Physiology with Student Consult Online Access |last=Hall|first=John E. |year=2011|edition=12th|publisher=Elsevier Saunders|location=Philadelphia|isbn=978-1-4160-4574-8|page=64|url=http://asia.elsevierhealth.com/media/us/samplechapters/9781416045748/Guyton%20&%20Hall%20Sample%20Chapter.pdf|accessdate=2011-03-22|archiveurl=http://web.archive.org/web/20110516132632/http://asia.elsevierhealth.com/media/us/samplechapters/9781416045748/Guyton%20&%20Hall%20Sample%20Chapter.pdf|archivedate=2011-05-16}}</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]],<ref>{{cite news|title=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|author=Michael P. Walsh, et all|url=http://biosupport.licor.com/docs/2005/BJ20050237.pdf}}</ref> excitation of neurons, up-regulation of [[gene expression]], or release of [[hormone]]s or [[neurotransmitter]]s.
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'''Voltage-dependent calcium channels''' (VDCC) are a group of [[voltage-gated ion channel|voltage-gated]] [[ion channel]]s found in excitable cells ([[neuron]]s, [[glial cell]]s, muscle cells, etc.) with a permeability to the ion [[calcium|Ca<sup>2+</sup>]], which plays a role in the [[membrane potential]]. VDCCs are involved in the release of [[neurotransmitter]]s and [[hormone]]s, [[muscle|muscular contraction]], excitability of neurons and [[gene expression]].
  
   
−
== Types of VDCC ==
 +
==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 |pmc=1760727}}</ref>
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*HVA (hight-voltage activated)
  
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**L-type
  
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**N-type
  
−
**P/Q-type
  
−
*R-type (intermediate voltage activated)
  
−
*T-type (low voltage activated)
  
   
  +
==Channel subunits==
−
== Therapeutic options ==
  
  ⚫
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, 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 muscle|skeletal]], [[smooth muscle|smooth]], and [[cardiac muscle]] and for hormone secretion in endocrine cells.
−
L-type [[calcium channel blocker]]s are used as antiarrhythmics or antihypertonics, depending on whether the drugs has higher affiniy to the heart (like verapamil) or to the vessels (nifedipine).
  
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T-type calcium channel blockers are used primary as antiepileptics, but also as anaesthetics or antipsychotics.
  
   
  +
{| class="wikitable" | style="text-align:center"
−
== Structure ==
  
  +
| '''Current Type''' || '''[[1,4-dihydropyridine]] sensitivity (DHP)''' || '''ω-[[conotoxin]] sensitivity (ω-CTX)''' || '''ω-agatoxin sensitivity (ω-AGA)'''
−
Voltage-dependent calcium channels are formed as a complex of several different subunits: &#945;1, &#945;2, &#946;, &#947;, and &#948;. The &#945;1 subunit is the one that decides most of the channel properties.
  
  +
|-
  +
|| 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 = 2|pages= 89–98 |year= 1995 |doi = 10.1016/0166-2236(95)93882-X|pmid= 7537420}}</ref>
   
  +
===α<sub>1</sub> Subunit===
−
==High voltage gated calcium channels==
  
  ⚫
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"/>
⚫
High voltage gated calcium channels (HVGCCs) are structurally homologous among varying types and are differentiated according to their physiological roles and/or inhibition by specific [[toxin]]s. High voltage gated calcium channels include the [[neuron|neural]] N-type channel blocked by &#969;-[[conotoxin]]s, the residual R-type channel involved in processes in the [[brain]] and [[muscle]], the closely related P/Q-type channel blocked by &#969;-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"
−
===&#945; 1 subunit===
  
  +
| '''Type''' || '''Voltage''' || '''α<sub>1</sub> subunit (gene name)''' || '''Associated subunits''' || '''Most often found in'''
⚫
The &#945; 1 subunit pore (190 kDa) is the primary subunit necessary for channel functioning in the HVGCC, and consists of the characteristic four homologous I-IV domains containing six transmembrane &#945;-helices each. The &#945; 1 subunit forms the Ca2+ selective pore which contains voltage sensing machinery and the drug/toxin binding sites. There are multiple &#945; 1 subunits that have been classified.
 
  +
|-
  +
| [[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}}) [[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, 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) || [[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
  +
|-
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| [[N-type calcium channel]] ("Neural"/"Non-L") || HVA (high-voltage-activated) || [[N-type calcium channel|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]] and peripheral nervous system.
  +
|-
  +
| [[R-type calcium channel]] ("Residual") || intermediate-voltage-activated || [[R-type calcium channel|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 || [[CACNA1G|Ca<sub>v</sub>3.1]] ({{Gene|CACNA1G}})<br /> [[CACNA1H|Ca<sub>v</sub>3.2]] ({{Gene|CACNA1H}})<br /> [[CACNA1I|Ca<sub>v</sub>3.3]] ({{Gene|CACNA1I}}) || || neurons, cells that have pacemaker activity, bone (osteocytes)
  +
|}
   
−
===&#946; subunit===
 +
===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:
⚫
The intracellular &#946; 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 &#946; subunit binds to the &#945; 1 subunit I-II cytoplasmic loop and regulates HVGCC activity. There are four known isoforms of the &#946; subunit.
 
  +
* [[CACNA2D1]] ({{Gene|CACNA2D1}}),
  +
* [[CACNA2D2]] ({{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.
⚫
It is hypothesized that the cytosolic &#946; subunit has the initial role of stabilizing the final &#945;1 subunit conformation and delivering it to cell membrane by its ability to mask an endoplasmic reticulum retention signal in the &#945;1 subunit. Bichet et al. discovered that the endoplasmic retention brake was contained in the I-II loop in the &#945;1 subunit that becomes masked when the &#946; subunit binds. Therefore the &#946; subunit functions initially to regulate the current density by controlling the amount of &#945; subunit expressed at the cell membrane.
  
   
  ⚫
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.
⚫
In addition to this initial role, the &#946; subunit has the added important functions of regulating the activation/ inactivation kinetics and increasing the peak amplitude in current of the &#945;1 subunit pore once it aids in the delivery of the &#945;1 subunit to the membrane. Singer et al. first discovered that the &#946; subunit had effects on the kinetics of the cardiac &#945;1C in Xenopus oocytes co-expressed with &#946; subunits. Later studies by Walker and De Waard further showed that the &#946; subunit acted as an important modulator of channel electrophysiological properties.
  
   
  +
===β Subunit===
⚫
Until very recently, the interaction between a highly conserved 18 AA region on the &#945;1 subunit intracellular linker between domains I and II (the Alpha Interaction Domain) and a region on the GK domain of the &#946; subunit (Alpha Interaction Domain Binding Pocket) was thought to be solely responsible for the regulatory effects by the &#946; subunit. Recently it has been discovered that the SH3 domain of the &#946; subunit also gives added regulatory effects on channel function, opening the possibility of the &#946; subunit having multiple regulatory interactions with the &#945;1 subunit pore. Furthermore, it was discovered that the AID does not contain the endoplasmic reticulum retention signal and is most likely located in other regions of the I-II &#945;1 subunit linker when mutations/deletions to the AID region gave the same expression at the plasma membrane and did not increase the current amplitudes.
  
  ⚫
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 | 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.
−
===&#945;2&#948; subunit===
  
⚫
The &#945;2&#948; are two subunits that are linked to each other via a disulfide bond and have a molecular weight of 170 kDa. The diversity of each &#945;2&#948; subunit arises due to alternative splicing of their gene. The &#945;2 is the extracellular glycosylated subunit that interacts the most with the &#945;1 subunit. The &#948; subunit has a single transmembrane region with a short intracellular portion which serves to anchor the protein in the plasma 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 laevis]] oocytes co-expressed with β subunits. The β subunit acts as an important modulator of channel electrophysiological properties.
⚫
Co-expression of the &#945;2&#948; enhances the level of expression of the &#945;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 affects are observed in the absence of the beta subunit whereas in other cases the co-expression of beta is required.
  
   
  ⚫
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.
⚫
The &#945;2&#948; subunit on the N-type Ca++ channel appears to be the binding site for at least two anticonvulsant drugs, [[gabapentin]] (Neurontin®) and [[pregabalin]] (Lyrica®), that also find use in treating chronic neuropathic pain.
  
   
−
===&#947; subunit===
 +
===γ Subunit===
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The &#947; subunit is associated with only some of the HVGCC complexes. The &#947; subunit glysoprotein (33 kDa) is composed of four transmembrane spanning helices. The &#947; subunits does not affect trafficking and for the most part is not required to regulate the channel complex. The &#947;1 subunit is associated with skeletal muscle while the &#947;2 and &#947;3 are associated with the P/Q and N-type channels.
 +
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}}),
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* [[CACNG2|γ2]] ({{Gene|CACNG2}}),
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* [[CACNG3|γ3]] ({{Gene|CACNG3}}),
  +
* [[CACNG4|γ4]] ({{Gene|CACNG4}}),
  +
* ({{Gene|CACNG5}}),
  +
* ({{Gene|CACNG6}}),
  +
* ({{Gene|CACNG7}}), and
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* ({{Gene|CACNG8}}).
   
 
===Muscle Physiology===
  
===Muscle Physiology===
   
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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| url = http://advan.physiology.org/cgi/content/full/27/4/201 | doi_brokendate = 2008-06-22 }}</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> | year= 2002 | publisher= Garland Science | location= New York, NY |language= |isbn= 0-8153-3218-1 |oclc= |doi= |id= |page= 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 influx 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).
 +
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| 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> | year= 2002 | publisher= Garland Science | location= New York, NY |language= |isbn= 0-8153-3218-1 |oclc= |doi= |id= |page= 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 influx 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 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<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.
 +
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 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<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.
   
 
==See also==
  
==See also==
−
*[[Ion channel]]s
 +
* [[Glutamate receptor]]s
  +
* [[Inositol triphosphate receptor]]
⚫
*[[Voltage-gated ion channel]]s
  
−
*[[Glutamate receptor]]s
 +
* [[Ion channel]]s
−
*[[NMDA receptor]]s
 +
* [[NMDA receptor]]s
  +
* [[Ryanodine receptor]]
−  
  ⚫
* [[Voltage-gated ion channel]]s
⚫
== External links ==
  
−
*[http://www.cf.ac.uk/biosi/staff/jacob/teaching/ionchan/ionchan5.html Ion Channels]
  
   
 
==References==
  
==References==
  +
{{Reflist|2}}
−
* [http://www.cja-jca.org/cgi/content/full/49/2/151 Calcium channels - basic aspects of their structure, function and gene encoding; anesthetic action on the channels - a review]. ''Canadian Journal of Anesthesia'', 49:151-164 (2002).
  
   
  ⚫
==External links==
  +
* [http://web.archive.org/web/20090704001440/http://www.biotrend.com/download/NET_BTReview%20040109.pdf Andrea Welling: Voltage-Dependent Calcium Channels, BIOTREND Reviews No. 04, January 2009, © 2009 BIOTREND Chemicals AG]
  +
*{{cite web | url = http://www.iuphar-db.org/IC/ReceptorFamiliesForward | title = Voltage-Gated Ion Channels | accessdate = | author = | authorlink = | coauthors = | date = | format = | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | pages = | language = | archiveurl = | archivedate = | quote = }}
  +
* {{MeshName|Calcium+Channels}}
  +
  +
{{Ion channels|g1}}
  +
  +
[[Category:Calcium]]
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[[Category:Electrophysiology]]
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[[Category:Integral membrane proteins]]
 
[[Category:Ion channels]]
  
[[Category:Ion channels]]
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[[Category:Membrane biology]]
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[[Category:Membranes]]
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Voltage-dependent calcium channels (VDCC) are a group of voltage-gated ion channels found in excitable cells (e.g., muscle, glial cells, neurons, etc.) with a permeability to the 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. Activation of particular VDCCs allows Ca2+ entry into the cell, which, depending on the cell type, results in muscular contraction,[4] excitation of neurons, up-regulation of gene expression, or release of hormones or neurotransmitters.

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.[5]

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

[6]

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]

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) Cav1.1 (CACNA1S)
Cav1.2 (CACNA1C) Cav1.3 (CACNA1D)
Cav1.4 (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) Cav2.1 (CACNA1A) α2δ, β, possibly γ Purkinje neurons in the cerebellum / Cerebellar granule cells
N-type calcium channel ("Neural"/"Non-L") HVA (high-voltage-activated) Cav2.2 (CACNA1B) α2δ/β1, β3, β4, possibly γ Throughout the brain and peripheral nervous system.
R-type calcium channel ("Residual") intermediate-voltage-activated Cav2.3 (CACNA1E) α2δ, β, possibly γ Cerebellar granule cells, other neurons
T-type calcium channel ("Transient") low-voltage-activated Cav3.1 (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:

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:

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.[7] 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:

Muscle Physiology

When a smooth muscle cell is depolarized, it causes opening of the voltage-gated, or L-type, calcium channels.[8][9] 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[8] 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.

See also

References

  1. ↑ 1.0 1.1 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.
  2. ↑ Yamakage M, Namiki A (2002). Calcium channels--basic aspects of their structure, function and gene encoding; anesthetic action on the channels--a review. Can J Anaesth 49 (2): 151–64.
  3. ↑ Hall, John E. (2011). Guyton and Hall Textbook of Medical Physiology with Student Consult Online Access, 12th, Philadelphia: Elsevier Saunders. URL accessed 2011-03-22.
  4. ↑ includeonly>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".
  5. ↑ Dolphin AC (2006). A short history of voltage-gated calcium channels. Br J Pharmacol 147 (Suppl 1): S56–62.
  6. ↑ Dunlap K, Luebke JI, Turner TJ (1995). Exocytotic Ca2+ channels in mammalian central neurons. Trends Neurosci. 18 (2): 89–98.
  7. ↑ 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.
  8. ↑ 8.0 8.1 Webb RC (2003). Smooth muscle contraction and relaxation. Adv Physiol Educ 27 (1-4): 201–6.
  9. ↑ Alberts, Bruce; Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002). Molecular Biology of the Cell, 4th, New York, NY: Garland Science.

External links


Membrane transport protein: ion channels
Ca Voltage-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 channel Nav1.4 - Nav1.5 - Nav1.7 - Epithelial sodium channel
K: Potassium channel Voltage-gated (KvLQT1, KvLQT2, KvLQT3, HERG, Shaker gene, KCNE1) - Calcium-activated (BK channel, SK channel) - Inward-rectifier (ROMK, KCNJ2) - Tandem pore domain
Cl: Chloride channel Cystic fibrosis transmembrane conductance regulator
Porin Aquaporin (1, 2, 3, 4)
Transient receptor potential TRPA - TRPC (TRPC6) - TRPM (TRPM6) - TRPML (Mucolipin-1) - TRPP - TRPV (TRPV1, TRPV6)
Other/general Gap junction - Stretch-activated ion channel - Ligand-gated ion channel - Voltage-gated ion channel - Cyclic nucleotide-gated ion channel - Two-pore channel
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