Structure and regulation of voltage-gated Ca2+ channels

Abstract

Voltage-gated Ca2+ channels mediate Ca2+ entry into cells in response to membrane depolarization. Electrophysiological studies reveal different Ca2+ currents designated L-, N-, P-, Q-, R-, and T-type. The high-voltage-activated Ca2+ channels that have been characterized biochemically are complexes of a pore-forming α1 subunit of ∼ 190-250 kDa; a transmembrane, disulfide-linked complex of α2 and δ subunits; an intracellular β subunit; and in some cases a transmembrane γ subunit. Ten α1 subunits, four α2δ complexes, four β subunits, and two γ subunits are known. The Cav1 family of α1 subunits conduct L-type Ca2+ currents, which initiate muscle contraction, endocrine secretion, and gene transcription, and are regulated primarily by second messenger-activated protein phosphorylation pathways. The CaV2 family of α1 subunits conduct N-type, P/Q-type, and R-type Ca2+ currents, which initiate rapid synaptic transmission and are regulated primarily by direct interaction with G proteins and SNARE proteins and secondarily by protein phosphorylation. The CaV3 family of α1 subunits conduct T-type Ca2+ currents, which are activated and inactivated more rapidly and at more negative membrane potentials than other Ca2+ current types. The distinct structures and patterns of regulation of these three families of Ca2+ channels provide a flexible array of Ca2+ entry pathways in response to changes in membrane potential and a range of possibilities for regulation of Ca2+ entry by second messenger pathways and interacting proteins.