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Interactions of Local Anesthetics with Voltage-gated Na+ Channels

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Abstract

Voltage-gated Na+ channels are dynamic transmembrane proteins responsible for the rising phase of the action potential in excitable membranes. Local anesthetics (LAs) and structurally related antiarrhythmic and anticonvulsant compounds target specific sites in voltage-gated Na+ channels to block Na+ currents, thus reducing excitability in neuronal, cardiac, or central nervous tissue. A high-affinity LA block is produced by binding to open and inactivated states of Na+ channels rather than to resting states and suggests a binding site that converts from a low- to a high-affinity conformation during gating. Recent findings using site-directed mutagenesis suggest that multiple S6 segments together form an LA binding site within the Na+ channel. While the selectivity filter may form the more extracellular-located part of this binding site, the role of the fast inactivation gate in LA binding has not yet been resolved. The receptor of the neurotoxin batrachotoxin (BTX) is adjacent to or even overlaps with the LA binding site. The close proximity of the LA and BTX binding sites to residues critical for inactivation, together with gating transitions through S6 segments, might explain the strong impact of LAs and BTX on inactivation of voltage-gated Na+ channels and might help elucidate the mechanisms underlying voltage- and frequency-dependent LA block.

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Acknowledgements

This work was supported by a Deutsche Forschungsgemeinschaft grant NA350/2-5 (Emmy Noether-Programm) (to C.N.) and by National Institutes of Health GM48090 (to G.K.W.).

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Authors and Affiliations

  1. Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, 91054, Germany

    C. Nau

  2. Department of Anesthesia, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA

    G.K. Wang

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  1. C. Nau
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  2. G.K. Wang
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Correspondence to C. Nau.

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Nau, C., Wang, G. Interactions of Local Anesthetics with Voltage-gated Na+ Channels. J Membrane Biol 201, 1–8 (2004). https://doi.org/10.1007/s00232-004-0702-y

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  • DOI: https://doi.org/10.1007/s00232-004-0702-y

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