Structure and Pharmacology of Voltage-Gated Sodium and Calcium Channels

• Published in: Annual review of pharmacology and toxicology Vol. 60; no. 1; pp. 133 - 154
• Main Authors: Catterall, William A, Lenaeus, Michael J, Gamal El-Din, Tamer M
• Format: Journal Article
• Language: English
• Published: United States Annual Reviews 06-01-2020
• Subjects: antiarrhythmic drugs; calcium antagonist drugs; calcium channels; Calcium Channels - chemistry; Calcium Channels - drug effects; Calcium Channels - metabolism; Channelopathies - drug therapy; Channelopathies - physiopathology; Cryoelectron Microscopy; Crystallography, X-Ray; Humans; local anesthetics; Molecular Targeted Therapy; sodium channels; Voltage-Gated Sodium Channels - chemistry; Voltage-Gated Sodium Channels - drug effects; Voltage-Gated Sodium Channels - metabolism; antiarrhythmic drugs; local anesthetics; sodium channels; calcium antagonist drugs; calcium channels
• ISSN: 0362-1642; 1545-4304
• DOI: 10.1146/annurev-pharmtox-010818-021757

Voltage-gated sodium and calcium channels are evolutionarily related transmembrane signaling proteins that initiate action potentials, neurotransmission, excitation-contraction coupling, and other physiological processes. Genetic or acquired dysfunction of these proteins causes numerous diseases, termed channelopathies, and sodium and calcium channels are the molecular targets for several major classes of drugs. Recent advances in the structural biology of these proteins using X-ray crystallography and cryo-electron microscopy have given new insights into the molecular basis for their function and pharmacology. Here we review this recent literature and integrate findings on sodium and calcium channels to reveal the structural basis for their voltage-dependent activation, fast and slow inactivation, ion conductance and selectivity, and complex pharmacology at the atomic level. We conclude with the theme that new understanding of the diseases and therapeutics of these channels will be derived from application of the emerging structural principles from these recent structural analyses.