alpha2delta

Alpha2delta is a family of auxiliary subunits of voltage-gated calcium channels (VGCCs). In humans, four genes—CACNA2D1, CACNA2D2, CACNA2D3, and CACNA2D4—encode alpha2delta proteins. The proteins are produced as a single precursor that is proteolytically cleaved into two components, alpha2 and delta, which remain linked by a disulfide bond and associate with the channel complex to influence trafficking and function of the pore-forming alpha1 subunit.

Structure and expression: Alpha2delta proteins contain an extracellular alpha2 domain, including a von Willebrand factor A (VWA) domain, and a relatively small delta portion that anchors to the membrane. Expression patterns vary by tissue and developmental stage, but all isoforms modulate VGCC trafficking and surface expression across neuronal and non-neuronal cells.

Function: By promoting trafficking of alpha1 to the plasma membrane and modulating channel gating, alpha2delta subunits increase calcium current density and can alter activation properties. They thus influence presynaptic calcium influx and neurotransmitter release, contributing to synaptic transmission and other Ca2+-dependent processes.

Pharmacology and clinical relevance: Alpha2delta subunits are high-affinity targets of gabapentinoid drugs such as gabapentin and pregabalin, which bind preferentially to alpha2delta-1 and alpha2delta-2. These agents reduce presynaptic calcium entry and neurotransmitter release, and are used to treat neuropathic pain and certain seizure disorders. Research continues into broader roles in pain, sleep, and mood regulation.

Genetics and disease: Variants and altered expression of CACNA2D genes have been linked to neurological conditions in humans and animal models, including epilepsy, ataxia, and migraine in some cases. The alpha2delta family remains a focus of studies on calcium channel physiology and its pharmacological modulation.