1. Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA
2. Laboratory of Toxicology, University of Leuven, 3000 Leuven, Belgium
3. CNRS UMR 6231, CRN2M, Institut Jean Roche, Université de la Méditerranée, Marseille Cedex 20, France

Correspondence to: Kenton J. Swartz¹ Correspondence and requests for materials should be addressed to K.J.S. (Email: swartzk@ninds.nih.gov).

Abstract

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.

1. Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA
2. Laboratory of Toxicology, University of Leuven, 3000 Leuven, Belgium
3. CNRS UMR 6231, CRN2M, Institut Jean Roche, Université de la Méditerranée, Marseille Cedex 20, France

Correspondence to: Kenton J. Swartz¹ Correspondence and requests for materials should be addressed to K.J.S. (Email: swartzk@ninds.nih.gov).

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