Biochemistry and physiology of voltage-gated calcium channel trafficking: a target for gabapentinoid drugs

Voltage-gated calcium channels are multi-pass transmembrane proteins that have key features that are essential for their correct function. For example, the concerted movement of the voltage sensor domains in response to depolarization is required to ensure the channels open over a particular range of voltages, essential for the physiological function of each of the 10 different mammalian calcium channels. Furthermore, their selectivity filter is required to maintain the Ca²⁺ selectivity of these channels. The auxiliary subunits, α₂δ and β, play important roles in aiding the channels to fold, traffic and function correctly. Of therapeutic importance, the α₂δ subunits are a drug target of the gabapentinoid α₂δ ligands, whose mechanism of action is now better understood. However, much is still unknown about how these calcium channels reach and are retained in specific locations, and how these processes are modified by various forms of modulation and synaptic plasticity.