TCDB is operated by the Saier Lab Bioinformatics Group

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.

References associated with 8.A.18 family:

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. 26460247
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. 22054663
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] 28290248
Cottrell, G.S., C.H. Soubrane, J.A. Hounshell, H. Lin, V. Owenson, M. Rigby, P.J. Cox, B.S. Barker, M. Ottolini, S. Ince, C.C. Bauer, E. Perez-Reyes, M.K. Patel, E.B. Stevens, and G.J. Stephens. (2018). CACHD1 is an α2δ-like protein that modulates Ca3 voltage-gated calcium channel activity. J. Neurosci. [Epub: Ahead of Print] 30181139
Dolphin, A.C., C.N. Wyatt, J. Richards, R.E. Beattie, P. Craig, J.H. Lee, L.L. Cribbs, S.G. Volsen, and E. Perez-Reyes. (1999). The effect of α2δ and other accessory subunits on expression and properties of the calcium channel α1γ. J. Physiol. 519: 35-45. 10432337
Gurnett, C.A., M. De Waard, and K.P. Campbell. (1996). Dual function of the voltage-dependent Ca2+ channel α2δ-subunit in current stimulation and subunit interaction. Neuron 16: 431-440. 8789958
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. 9218497
Isom, L.L., D.S. Ragsdale, K.S. De Jongh, R.E. Westenbroek, B.R. Reber, T. Scheuer, and W.A. Catterall. (1995). Structure and function of the β2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motif. Cell 83: 433-442. 8521473
Kerov, V., J.G. Laird, M.L. Joiner, S. Knecht, D. Soh, J. Hagen, S.H. Gardner, W. Gutierrez, T. Yoshimatsu, S. Bhattarai, T. Puthussery, N.O. Artemyev, A.V. Drack, R.O. Wong, S.A. Baker, and A. Lee. (2018). αδ-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses. J. Neurosci. 38: 6145-6160. 29875267
Kim, H.L., H. Kim, P. Lee, R.G. King, and H. Chin. (1992). Rat brain expresses an alternatively spliced form of the dihydropyridine-sensitive L-type calcium channel α2-subunit. Proc. Natl. Acad. Sci. USA 89: 3251-3255. 1314383
Page, K.M., V.M. Gumerov, S. Dahimene, I.B. Zhulin, and A.C. Dolphin. (2023). The importance of cache domains in αδ proteins and the basis for their gabapentinoid selectivity. Channels (Austin) 17: 2167563. 36735378
Peng, C., L. Li, M.D. Zhang, C. Bengtsson Gonzales, M. Parisien, I. Belfer, D. Usoskin, H. Abdo, A. Furlan, M. Häring, F. Lallemend, T. Harkany, L. Diatchenko, T. Hökfelt, J. Hjerling-Leffler, and P. Ernfors. (2017). miR-183 cluster scales mechanical pain sensitivity by regulating basal and neuropathic pain genes. Science 356: 1168-1171. 28572455
Song L., Espinoza-Fuenzalida IA., Etheridge S., Jones OT. and Fitzgerald EM. (201). The R-Domain: Identification of an N-terminal Region of the alpha2delta-1 Subunit Which is Necessary and Sufficient for its Effects on Cav2.2 Calcium Currents. Curr Mol Pharmacol. 8(2):169-79. 25966687
Song, X., W. Zhang, S. Jia, S. Wang, G. Wang, F. Xiong, and H. Li. (2021). Differential Proteomics Analysis of the Subcutaneous Connective Tissues in Alcian Blue Tracks along Conception Vessel and Adjacent Nonmeridian in Rats. Evid Based Complement Alternat Med 2021: 5550694. 34035822
Tuluc, P., T. Theiner, N. Jacobo-Piqueras, and S.M. Geisler. (2021). Role of High Voltage-Gated Ca Channel Subunits in Pancreatic β-Cell Insulin Release. From Structure to Function. Cells 10:. 34440773
Zhang, J., L. Wu, Z. Li, and G. Fu. (2017). miR-1231 exacerbates arrhythmia by targeting calciumchannel gene in myocardial infarction. Am J Transl Res 9: 1822-1833. 28469787