Cacna2d2

Cacna2d2, also known as alpha-2/delta-2, is a subunit of voltage-gated calcium channels encoded by the CACNA2D2 gene in humans. It is one of the auxiliary alpha2delta subunits that associate with the pore-forming alpha1 subunits of Cav channels. The protein is synthesized as a single precursor that is proteolytically cleaved into an extracellular alpha2 portion and a delta segment that remains linked to the membrane-bound portion by a disulfide bond.

The alpha2delta subunits are thought to promote trafficking of Cav channels to the plasma membrane and to modulate channel properties, including current density and gating, thereby influencing calcium entry and neurotransmitter release at synapses. They interact with the primary alpha1 subunits and with other auxiliary subunits to form functional channel complexes that shape neuronal excitability and synaptic transmission.

Cacna2d2 is expressed throughout the nervous system, with varying levels across brain regions. In addition to its normal role in channel trafficking and regulation, alpha2delta-2 participates in synaptic plasticity processes that rely on tightly controlled calcium signaling. The subunit is also a pharmacologic target of gabapentinoid drugs.

Clinical significance of CACNA2D2 mutations has been described in a limited number of cases, with associations to epileptic and neurodevelopmental phenotypes that can include cerebellar ataxia in some individuals. Animal models, such as mice with altered Cacna2d2 function, show motor coordination deficits and changes in seizure susceptibility, supporting a role for alpha2delta-2 in cerebellar function and network excitability. Gabapentinoids exert part of their therapeutic effects by binding to alpha2delta subunits, including alpha2delta-2, to reduce presynaptic calcium influx and dampen excitatory transmission.