Voltage-gated Ca²⁺ (Ca_V) channels are ubiquitously expressed and function as Ca²⁺ conducting pores in the plasma membrane¹. On the basis of their voltage activation properties, Ca_V channels can be further divided into two broad groups: the low (T-type) and high (L, N, P, Q and R-type) threshold-activated channels². HVA channels are heteromultimers composed of four independently encoded proteins, the pore-forming α1 subunit, which triggers Ca²⁺ flow across the membrane, and the auxiliary subunits α2δ, γ, and β³. The Ca²⁺ channel α2δ subunit is a heavily glycosylated protein that is encoded by a single gene and post-translationally cleaved to yield α2 and δ subunits linked by a disulfide bond with a single transmembrane segment⁴.  The α2δ subunit regulates many functional aspects of Ca²⁺ channels, such as gating, regulating voltage dependent kinetics, and increasing functional channel density on the plasma membrane⁵.

There are four proteins that comprise Ca_Vα2δ: Ca_Vα2δ1, Ca_Vα2δ2, Ca_Vα2δ3 and Ca_Vα2δ4⁶. The Ca_Vα2δ3 subunit is predominantly expressed in neuronal tissue. The Ca_Vα2δ3 subunit regulates all classes of HVA calcium channels. The Caα2δ3 subunits in the nerve terminal function in synaptic morphogenesis and cytoskeletal organization, and that this role is independent of their function in α1 subunit localization and physiology.

Ca_Vα2δ3 is likely to be the primary presynaptic α2δ isoform mediating morphological development of the neuromuscular junction (NMJ), since null alleles have such a large effect on NMJ development and abolish all action-potential evoked transmission⁷. Recent study shows that methylation-dependent transcriptional silencing of Ca_Vα2δ3 may contribute to the metastatic phenotype of breast cancer⁸.