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Voltage-dependent calcium channel



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.

Contents

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 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
[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]

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, 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/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") HVA (high voltage activated) Cav2.2 (CACNA1B) α2δ/β1, β3, β4, possibly γ Throughout the brain
R-type calcium channel 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:

  • (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 (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.[4] 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 (CACNG2),
  • (CACNG3),
  • (CACNG4),
  • (CACNG5),
  • (CACNG6),
  • (CACNG7), and
  • (CACNG8).

Muscle Physiology

When a smooth muscle cell is depolarized, it causes opening of the voltage-gated, or 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 infux 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 the first reference below for an illustration of the signalling cascade involving L-type calcium channels in smooth muslce; an electronic link is also provided to the full text.)

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 caclium channel permits influx of calcium into the cell. The calcium binds to the calcium release channels (RYR's) in the SR, opening them; this phenomenon is called "calcium-induced calcium release," or CICR. However the RYR's 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.

Webb, R. C. (2003). Smooth Muscle Contraction and Relaxation. Advances in Physiology Education, 27, 201-206.

Alberts, B. et al. (2002) Molecular Biology of the Cell. 4th Edition. Garland Science, NY, NY.

References

  1. ^ 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.
  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. ^ 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

 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Voltage-dependent_calcium_channel". A list of authors is available in Wikipedia.
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