8.A.18 The Ca2+ Channel Auxiliary Subunit α2δ Types 1-4 (CCA-α2δ) Family

The CCA-α2δ family consists of animal proteins with a single transmembrane segment. The proteins of this family are encoded as single polypepetides, which are cleaved into α and δ subunits that are then joined together via a disulfide bridge. Members of the α2δ family are transmembrane auxiliary subunits for calcium channels expressed in a wide variety of tissues including brain, heart, and skeletal muscle. Alternative splicing gives rise to the extensive structural and functional diversity observed for these subunits (Kim et al., 1992). Some are found to impact the expression of the pore-forming subunit (Dolphin et al., 1999). The mRNA sequence encoding the α2 subunit was first determined in association with a dihydropyridine-sensitive calcium channel. The δ-subunit has a single transmembrane segment and a short link to the α2 portion of the subunit. α2 contains an extracellular portion of the functional complex that interacts with the pore-forming principal subunit and increases functional diversity (Gurnett et al., 1996; 1997). The δ domain of the protein was shown to modulate the gating properties of the high voltage-activated calcium channels. A disulfide bridge is essential for structure and function (Calderón-Rivera et al., 2011).

The large CCA-α2δ proteins each contain a domain that show significant sequence similarity and similar apparent topologies with EClC family members (TC# 1.A.13). Homologues are found ubiquitously including in prokaryotes. Because these domains appear to be hydrophilic domains, they probably do not form the channel of EClC family members.

The presence of the α2δ subunit facilitates activation of voltage-sensitive Ca2+ channels (VSCC). Hence, one might expect that drugs that bind to and inhibit the α2δ subunit, e.g. gabapentin and pregabalin, would be protective against absence epilepsy, and that mice lacking the α2δ subunit would be resistant to evoked absence seizures, but this is not the case, suggesting that these subunits have additional functions (Celli et al. 2017).

The pancreatic islets of Langerhans secrete several hormones critical for glucose homeostasis. The beta-cells, the major cellular component of the pancreatic islets, secrete insulin, the only hormone capable of lowering the plasma glucose concentration. The counter-regulatory hormone glucagon is secreted by the alpha-cells while delta-cells secrete somatostatin that via paracrine mechanisms regulates the alpha- and beta-cell activities. These three peptide hormones are packed into secretory granules that are released through exocytosis following a local increase in the intracellular Ca2+ concentration. The high voltage-gated Ca2+ channels (HVCCs) occupy a central role in pancreatic hormone release both as a source of Ca2+ required for excitation-secretion coupling as well as a scaffold for the release machinery. HVCCs are multi-protein complexes composed of the main pore- forming transmembrane alpha1 and the auxiliary intracellular beta, extracellular alpha2delta, and transmembrane gamma subunits. Tuluc et al. 2021 reviewed the current understanding regarding the role of all HVCC subunits expressed in pancreatic beta-cell on electrical activity, excitation-secretion coupling, and beta-cell mass.



Baeza-Richer, C., E. Arroyo-Pardo, R. Blanco-Rojo, L. Toxqui, A. Remacha, M.P. Vaquero, and A.M. López-Parra. (2015). Genetic contribution to iron status: SNPs related to iron deficiency anaemia and fine mapping of CACNA2D3 calcium channel subunit. Blood Cells Mol Dis 55: 273-280.

Calderon-Rivera A., Andrade A., Hernandez-Hernandez O., Gonzalez-Ramirez R., Sandoval A., Rivera M., Gomora JC. and Felix R. (2012). Identification of a disulfide bridge essential for structure and function of the voltage-gated Ca(2+) channel alpha(2)delta-1 auxiliary subunit. Cell Calcium. 51(1):22-30.

Celli, R., I. Santolini, M. Guiducci, G. van Luijtelaar, P. Parisi, P. Striano, R. Gradini, G. Battaglia, R.T. Ngomba, and F. Nicoletti. (2017). The Α2δ Subunit and Absence Epilepsy: Beyond Calcium Channels? Curr Neuropharmacol. [Epub: Ahead of Print]

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Gurnett, C.A., R. Felix, and K.P. Campbell. (1997). Extracellular interaction of the voltage-dependent Ca2+ channel α2δ- and α1-subunits. J. Biol. Chem. 272: 18508-18512.

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TC#NameOrganismal TypeExample

Dihydropyridine-sensitive L-type, Ca2+ channel subunit, Cav2.2, α2δ subunit 1, CACNA2D1, NL2A, CCHL2A, MHS3.  An N-terminal region (the R-domain) is necessary and sufficient for Cav2.2 regulation (Song et al. 2015). This subunit is regulated at the transcriptional level by microRNA, MiR-183, which thereby regulates nociceptive basal and neuropathic pain (Peng et al. 2017). It is upregulated in the low hydraulic resistance channel (LHRC) along meridians (Song et al. 2021).


CACNA2D1 of Homo sapiens (P54289)


TC#NameOrganismal TypeExample

Ca2+ channel, α2δ subunit 2, CACNA2D2 (Zhang et al. 2017).


CACNA2D2 of Homo sapiens (Q9NY47)


CACHD1 of 1274 aas and 2 TMSs.  CACHD1 is structurally an α2δ-like protein that functionally increases CaV3 calcium current. CACHD1 increases the presence of CaV3.1 (TC# 1.A.1.11.12) at the cell surface, forms complexes with CaV3.1, and causes an increase in channel open probability. In hippocampal neurons, CACHD1 causes increases in neuronal firing. Thus, CACHD1 modulates CaV3 activity (Cottrell et al. 2018).

CACHD1 of Homo sapiens


TC#NameOrganismal TypeExample

Ca2+ channel, voltage-dependent, α2δ subunit 3, CACNA2D3 of 1091 aas and 2 - 4 TMSs (Baeza-Richer et al. 2015).


CACNA2D3 of Homo sapiens (Q8IZS8)


Voltage-gated Ca2+ channel α2δ subunit 4, CACNA2D4 (Kerov et al. 2018). The importance of the cache domains in α2δ proteins and the basis for their gabapentinoid selectivity has been discussed (Page et al. 2023).


CACNA2D4 of Homo sapiens (Q8IZS9)


TC#NameOrganismal TypeExample