Voltage-gated calcium channels: their discovery, function and importance as drug targets

This review will first describe the importance of Ca²⁺ entry for function of excitable cells, and the subsequent discovery of voltage-activated calcium conductances in these cells. This finding was rapidly followed by the identification of multiple subtypes of calcium conductance in different tissues. These were initially termed low- and high-voltage activated currents, but were then further subdivided into L-, N-, PQ-, R and T-type calcium currents on the basis of differing pharmacology, voltage-dependent and kinetic properties, and single channel conductance. Purification of skeletal muscle calcium channels allowed the molecular identification of the pore-forming and auxiliary α₂δ, β and ϒ subunits present in these calcium channel complexes. These advances then led to the cloning of the different subunits, which permitted molecular characterisation, to match the cloned channels with physiological function. Studies with knockout and other mutant mice then allowed further investigation of physiological and pathophysiological roles of calcium channels. In terms of pharmacology, cardiovascular L-type channels are targets for the widely used antihypertensive 1,4-dihydropyridines and other calcium channel blockers, N-type channels are a drug target in pain, and α₂δ-1 is the therapeutic target of the gabapentinoid drugs, used in neuropathic pain. Recent structural advances have allowed a deeper understanding of Ca²⁺ permeation through the channel pore and the structure of both the pore-forming and auxiliary subunits. Voltage-gated calcium channels are subject to multiple pathways of modulation by G-protein and second messenger regulation. Furthermore their trafficking pathways, subcellular localisation and functional specificity are the subjects of active investigation.