Voltage-dependent calcium channel subunit alpha-2-delta-2 (CACNA2D2)

The Voltage-dependent calcium channel subunit alpha-2-delta-2 (CACNA2D2) is an auxiliary protein that plays a vital role in regulating the functional expression and biophysical properties of voltage-gated calcium channels (VGCCs) within the central nervous system and the heart (UniProt Q9NY47). It is encoded by the CACNA2D2 gene and consists of an extracellular alpha-2 domain disulfide-bonded to a transmembrane delta domain, which together facilitate the trafficking of pore-forming alpha-1 subunits to the cell surface (PubMed: 22448436). Biologically, this subunit is essential for controlling calcium current density and supporting synaptogenesis and neurotransmitter release. In clinical medicine, mutations in CACNA2D2 are linked to severe neurological phenotypes, including early infantile epileptic encephalopathy type 11 and spinocerebellar ataxia (OMIM: 613722). Pharmacologically, CACNA2D2 is a high-affinity binding site for gabapentinoid drugs like gabapentin and pregabalin, which are used to treat epilepsy and neuropathic pain by dampening neuronal hyperexcitability through calcium channel modulation (PubMed: 15302681).

Other names

Alpha-2-delta-2Calcium channel, voltage-dependent, alpha 2/delta subunit 2Voltage-gated calcium channel subunit alpha-2/delta-2CACNA2D2

Gabapentinoid drugs bind with high affinity to the alpha-2-delta subunits (specifically isoforms 1 and 2). This binding inhibits the trafficking of voltage-gated calcium channels to the plasma membrane and modulates the release of excitatory neurotransmitters, such as glutamate, by interfering with the interaction between the channel and the synaptic vesicle machinery.