Deconstructing voltage sensor function and pharmacology in sodium channels

Voltage-activated sodium (Na v ) channels are crucial for the generation and propagation of nerve impulses, and as such are widely targeted by toxins and drugs. The four voltage sensors in Na v channels have distinct amino acid sequences, raising fundamental questions about their relative contributions to the function and pharmacology of the channel. Here we use four-fold symmetric voltage-activated potassium (K v ) channels as reporters to examine the contributions of individual S3b–S4 paddle motifs within Na v channel voltage sensors to the kinetics of voltage sensor activation and to forming toxin receptors. Our results uncover binding sites for toxins from tarantula and scorpion venom on each of the four paddle motifs in Na v channels, and reveal how paddle-specific interactions can be used to reshape Na v channel activity. One paddle motif is unique in that it slows voltage sensor activation, and toxins selectively targeting this motif impede Na v channel inactivation. This reporter approach and the principles that emerge will be useful in developing new drugs for treating pain and Na v channelopathies. Sodium channels unmasked Na v sodium ion channels in nerve and muscle cells open and close, or 'gate', in response to changes in transmembrane voltage. They are crucial for the production of nerve impulses, and are targets for many toxins and drugs. Unlike voltage-gated K + channels, made up of four subunits containing identical voltage-sensing domains, Na v channels derive from one gene and contain four non-identical voltage-sensing domains. Bosmans et al . utilized symmetrical K + channels as 'reporters' to reveal the properties of various Na + channel voltage sensors transplanted into a K + channel core. They find that the paddle domain is important for Na + channel function, and that toxin–paddle interactions are highly specific.