Voltage-dependent calcium channel

# Overview
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+.  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, 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: 1, 2, 1-4, and . The 1 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 -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 -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.

## 1 Subunit
The 1 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 -helices each. The 1 subunit forms the Ca2+ selective pore, which contains voltage-sensing machinery and the drug/toxin-binding sites. A total of ten 1 subunits that have been identified in humans:

## 2 Subunit
The 2 gene forms two subunits 2 and  (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 2 is the extracellular glycosylated subunit that interacts the most with the 1 subunit. The  subunit has a single transmembrane region with a short intracellular portion, which serves to anchor the protein in the plasma membrane.  There are 4 2 genes:
- CACNA2D1 (CACNA2D1),
- (CACNA2D2),
- (CACNA2D3),
- (CACNA2D4).
Co-expression of the 2 enhances the level of expression of the 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 effects are observed in the absence of the beta subunit, whereas, in other cases, the co-expression of beta is required.
The 2-1 and 2-2 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.

##  Subunit
The intracellular  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  subunit binds to the 1 subunit I-II cytoplasmic loop and regulates HVGCC activity. There are four known isoforms of the  subunit:
- CACNB1 (CACNB1),
- CACNB2 (CACNB2),
- CACNB3 (CACNB3),
- CACNB4 (CACNB4).
It is hypothesized that the cytosolic  subunit has a major role in stabilizing the final 1 subunit conformation and delivering it to the cell membrane by its ability to mask an endoplasmic reticulum retention signal in the 1 subunit. The endoplasmic retention brake is contained in the I-II loop in the 1 subunit that becomes masked when the  subunit binds.  Therefore the  subunit functions initially to regulate the current density by controlling the amount of 1 subunit expressed at the cell membrane.
In addition to this trafficking role, the  subunit has the added important functions of regulating the activation and inactivation kinetics, and hyperpolarizing the voltage-dependence for activation of the 1 subunit pore, so that more current passes for smaller depolarizations. The  subunit has effects on the kinetics of the cardiac 1C in Xenopus oocytes co-expressed with  subunits.  The  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 1 subunit intracellular linker between domains I and II (the Alpha Interaction Domain, AID) and a region on the GK domain of the  subunit (Alpha Interaction Domain Binding Pocket) was thought to be solely responsible for the regulatory effects by the  subunit.  Recently, it has been discovered that the SH3 domain of the  subunit also gives added regulatory effects on channel function, opening the possibility of the  subunit having multiple regulatory interactions with the 1 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 1 subunit linker.

##  Subunit
The 1 subunit is known to be associated with skeletal muscle VGCC complexes, but the evidence is inconclusive regarding other subtypes of calcium channel. The 1 subunit glycoprotein (33 kDa) is composed of four transmembrane spanning helices. The 1 subunit does not affect trafficking, and, for the most part, is not required to regulate the channel complex.  However, 2, 3, 4 and 8 are also associated with AMPA glutamate receptors.
There are 8 genes for gamma subunits:
- 1 (CACNG1),
- 2 (CACNG2),
- 3 (CACNG3),
- 4 (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 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 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, 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.