Regulation of high-voltage-activated Ca²⁺ channel function, trafficking, and membrane stability by auxiliary subunits

Voltage-gated Ca²⁺ (Ca_V) channels mediate Ca²⁺ ions influx into cells in response to depolarization of the plasma membrane. They are responsible for initiation of excitation-contraction and excitation-secretion coupling, and the Ca²⁺ that enters cells through this pathway is also important in the regulation of protein phosphorylation, gene transcription, and many other intracellular events. Initial electrophysiological studies divided Ca_V channels into low-voltage-activated (LVA) and high-voltage-activated (HVA) channels. The HVA Ca_V channels were further subdivided into L, N, P/Q, and R-types which are oligomeric protein complexes composed of an ion-conducting Ca_Vα₁ subunit and auxiliary Ca_Vα₂δ, Ca_Vβ, and Ca_Vγ subunits. The functional consequences of the auxiliary subunits include altered functional and pharmacological properties of the channels as well as increased current densities. The latter observation suggests an important role of the auxiliary subunits in membrane trafficking of the Ca_Vα₁ subunit. This includes the mechanisms by which Ca_V channels are targeted to the plasma membrane and to appropriate regions within a given cell. Likewise, the auxiliary subunits seem to participate in the mechanisms that remove Ca_V channels from the plasma membrane for recycling and/or degradation. Diverse studies have provided important clues to the molecular mechanisms involved in the regulation of Ca_V channels by the auxiliary subunits, and the roles that these proteins could possibly play in channel targeting and membrane Stabilization.