Voltage-gated sodium channels initiate action potentials in nerve, muscle and other excitable cells. Early physiological studies described sodium selectivity, voltage-dependent activation and fast inactivation, and developed conceptual models for sodium channel function. This review article follows the topics of my 2013 Sharpey-Schafer Prize Lecture and gives an overview of research using a combination of biochemical, molecular biological, physiological and structural biological approaches that have elucidated the structure and function of sodium channels at the atomic level. Structural models for voltage-dependent activation, sodium selectivity and conductance, drug block and both fast and slow inactivation are discussed. A perspective for the future envisions new advances in understanding the structural basis for sodium channel function and the opportunity for structure-based discovery of novel therapeutics.

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