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Deconstructing voltage sensor function and pharmacology in sodium channels

Nature volume 456, pages 202–208 (2008)Cite this article

Abstract

Voltage-activated sodium (Nav) 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 Nav 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 (Kv) channels as reporters to examine the contributions of individual S3b–S4 paddle motifs within Nav 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 Nav channels, and reveal how paddle-specific interactions can be used to reshape Nav channel activity. One paddle motif is unique in that it slows voltage sensor activation, and toxins selectively targeting this motif impede Nav channel inactivation. This reporter approach and the principles that emerge will be useful in developing new drugs for treating pain and Nav channelopathies.

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Figure 1: Transfer of the voltage sensor paddle motifs from rNa v 1.2a to K v 2.1.
Figure 2: Sensitivity of rNa v 1.2a paddle chimaeras to extracellular toxins.
Figure 3: Scanning mutagenesis of Na v channel paddle motifs.
Figure 4: Reconstitution of paddle mutants into rNa v 1.2a and their effects on toxin–channel interactions.
Figure 5: Kinetics of opening and closing for rNa v 1.2a/K v 2.1 chimaeras.
Figure 6: Identifying a tarantula toxin selective for the paddle motif in domain IV.

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Acknowledgements

We thank J. W. Kyle, D. A. Hanck and A. L. Goldin for the rNav1.2a, rNav1.4 and β1 clones, C. Deutsch for Kv1.3, M. M. Smith for GxTx-1E, K. M. Blumenthal and J. B. Herrington for ProTx-II, L. D. Possani for a sample of TsVII, the NINDS DNA sequencing facility for DNA sequencing, and the NINDS protein sequencing facility for mass spectrometry and peptide sequencing. We thank A. A. Alabi for helping with Kv and Nav channel alignments and T.-H. Chang for assistance with Nav channel mutants. We also thank A. A. Alabi, M. Holmgren, M. Mayer, M. Milescu, J. Mindell, A. Plested, S. Silberberg and members of the Swartz laboratory for discussions. This work was supported by the Intramural Research Program of the NINDS, NIH (K.J.S.) and by an NIH-FWO postdoctoral fellowship (F.B.).

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Authors and Affiliations

  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 ,

    Frank Bosmans & Kenton J. Swartz

  2. Laboratory of Toxicology, University of Leuven, 3000 Leuven, Belgium

    Frank Bosmans

  3. CNRS UMR 6231, CRN2M, Institut Jean Roche, Université de la Méditerranée, Marseille Cedex 20, France

    Marie-France Martin-Eauclaire

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Correspondence to Kenton J. Swartz.

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Bosmans, F., Martin-Eauclaire, MF. & Swartz, K. Deconstructing voltage sensor function and pharmacology in sodium channels. Nature 456, 202–208 (2008). https://doi.org/10.1038/nature07473

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