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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, suggestioni that these subunits have additional functions (Celli et al. 2017).

References associated with 8.A.18 family:

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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
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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. 9218497
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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
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
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