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

Abstract

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.

Keywords: calcium; channel; heart; neuron; second messenger; voltage.

Figure 1.

Some key figures in the early discovery of calcium channels and their pharmacology: (a) Bernard Katz, (b) Susumu Hagiwara, (c) Paul Fatt, (d) Bernard Ginsborg (right) demonstrating equipment similar to that used to record crustacean muscle action potentials, (e) Harald Reuter and (f) Albrecht Fleckenstein. (c) is taken from a photograph (1978) by Martin Rosenberg, the Physiological Society; reproduced with permission; (a), (b) and (f) are reproduced from with permission from Richard W. Tsien (Barrett and Tsien, 2004); (d) is reproduced with permission from Bernard Ginsborg, who died this year (1925–2018).

Figure 2.

Single calcium channels with different properties, and topology of the channels. (a) Identification of a third component of voltage-gated calcium channels (N-type) from the biophysical properties of single channel currents observed in cell-attached patches on dorsal root ganglion neurons. Redrawn from Nowycky et al. (1985). TP: test potential; HP: holding potential. Reproduced with thanks to Richard W. Tsien. (b) Diagram of α₁ subunit topology and calcium channel subunit structure, also showing α₂δ (purple) and β (blue). ϒ₁ is only present in skeletal muscle calcium channel complexes. S4 voltage sensors in each α₁ domain are represented by red transmembrane segments. Yellow denotes S5 and S6 pore transmembrane segments in each domain.

Figure 3.

Inhibitory G-protein modulation of neuronal calcium channels. (a) Action potential (prolonged by K⁺ channel blockade), recorded from dorsal root ganglion neuron, showing the control, inhibition by the GABA-B agonist baclofen (100 μM) and recovery (from Figure 7 of Dolphin et al. (1986)). (b) Calcium channel currents recorded from dorsal root ganglion neuron, showing inhibition by baclofen (bac, 50 μM) (Dolphin et al., 1989). (c) Calcium channel currents recorded from Xenopus laevis oocytes injected with Ca_V2.2/β3/α₂δ-1 and the dopamine D2 receptor, showing inhibition by the D2 agonist quinpirole (100 nM) (replotted from Figure 2(e) of Canti et al. (2000).