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.