Structural Pharmacology of Voltage-Gated Sodium Channels

Voltage-gated sodium (NaV) channels initiate and propagate action potentials in excitable tissues to mediate key physiological processes including heart contraction and nervous system function. Accordingly, NaV channels are major targets for drugs, toxins and disease-causing mutations. Recent breakthroughs in cryo-electron microscopy have led to the visualization of human NaV1.1, NaV1.2, NaV1.4, NaV1.5 and NaV1.7 channel subtypes at high-resolution. These landmark studies have greatly advanced our structural understanding of channel architecture, ion selectivity, voltage-sensing, electromechanical coupling, fast inactivation, and the molecular basis underlying NaV channelopathies. NaV channel structures have also been increasingly determined in complex with toxin and small molecule modulators that target either the pore module or voltage sensor domains. These structural studies have provided new insights into the mechanisms of pharmacological action and opportunities for subtype-selective NaV channel drug design. This review will highlight the structural pharmacology of human NaV channels as well as the potential use of engineered and chimeric channels in future drug discovery efforts.