Voltage-gated calcium channels (VGCCs), also known as 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) which are permeable to calcium ion Ca2+. Since these channels are slightly permeable to sodium ions, they are also called Ca2+–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, VGCCs are normally closed. They are activated (i.e.: opened) at depolarized membrane potentials and this is the source of the "voltage-gated" epithet. The concentration of calcium (Ca2+ ions) is normally several thousand times higher outside the cell than inside. Activation of particular VGCCs allows a Ca2+ influx 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. VGCCs 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 VGCCs correlated with plasma aldosterone levels of patients. Excessive activation of VGCCs 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.
Structure Voltage-gated 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.
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.
Reference for the table can be found at Dunlap, Luebke and Turner (1995).
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: α1 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 evolutionarily related to VGCCs. 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). VGCCs are subject to rapid inactivation, which is thought to consist of 2 components: voltage-gated (VGI) and calcium-gated (CGI). These are distinguished by using either Ba2+ or Ca2+ as the charge carrier in the external recording solution (in vitro). The CGI component is attributed to the binding of the Ca2+-binding signaling protein calmodulin (CaM) to at least 1 site on the channel, as Ca2+-null CaM mutants abolish CGI in L-type channels. Not all channels exhibit the same regulatory properties and the specific details of these mechanisms are still largely unknown.
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 (CACNA2D1), CACNA2D2 (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 gabapentinoids. This drug class comprises compounds that are chemically derivatives of GABA. That includes drugs like gabapentin (Neurontin) and pregabalin (Lyrica), which find use in treating chronic neuropathic pain and Anxiety disorders, but also the skeletal muscle relaxant Baclofen (Lioseral), Phenibut and Mirogabalin. All these compounds possess varying degrees of binding affinity with the α2δ, though Baclofen and Phenibut have a higher affinity for the GABAB receptor relative to the α2δ subunits.
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 genes for the β subunit:
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