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The conformational cycle of a prototypical voltage-gated sodium channel

Abstract

Electrical signaling was a dramatic development in evolution, allowing complex single-cell organisms like Paramecium to coordinate movement and early metazoans like worms and jellyfish to send regulatory signals rapidly over increasing distances. But how are electrical signals generated in biology? In fact, voltage-gated sodium channels conduct sodium currents that initiate electrical signals in all kingdoms of life, from bacteria to man. They are responsible for generating the action potential in vertebrate nerve and muscle, neuroendocrine cells, and other cell types1,2. Because of the high level of conservation of their core structure, it is likely that their fundamental mechanisms of action are conserved as well. Here we describe the complete cycle of conformational changes that a bacterial sodium channel undergoes as it transitions from resting to activated/open and inactivated/closed states, based on high-resolution structural studies of a single sodium channel. We further relate this conformational cycle of the ancestral sodium channel to the function of its vertebrate orthologs. The strong conservation of amino acid sequence and three-dimensional structure suggests that this model, at a fundamental level, is relevant for both prokaryotic and eukaryotic sodium channels, as well as voltage-gated calcium and potassium channels.

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Fig. 1: Structure of NaVAb7.
Fig. 2: Comparison of NaVAb structures in the resting state and the activated state7,10.
Fig. 3: The activation gate and the pore in resting, activated, and inactivated states7,8,9,10.
Fig. 4: Mammalian NaV and bacterial NaVAb are structurally conserved.
Fig. 5: Drug access to the pore via the hydrophobic fenestrations.

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Acknowledgements

Research from the authors’ laboratories presented here was supported by Research Grants from the National Institutes of Health (R01 HL112808 to W.A.C. and N.Z.; R01 NS15751 to W.A.C., and R35 NS111573 to W.A.C.) and by the Howard Hughes Medical Institute (N.Z.). We thank J. Li (Pharmacology, University of Washington) for editorial assistance.

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W.A.C. wrote the first draft of the manuscript, G.W. prepared the figures, and all three authors revised and finalized the text and figures.

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Correspondence to William A. Catterall.

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Supplementary information

Supplementary Video 1

Conformational transitions of NaVAb from the resting to the activated states from a transmembrane view.

Supplementary Video 2

Conformational transitions of NaVAb from the resting to the activated states from an intracellular view.

Supplementary Video 3

Conformational transitions of NaVAb from the resting to the activated to the inactivated states from a transmembrane view.

Supplementary Video 4

Conformational transitions of NaVAb from the resting to the activated to the inactivated states from an intracellular view.

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Catterall, W.A., Wisedchaisri, G. & Zheng, N. The conformational cycle of a prototypical voltage-gated sodium channel. Nat Chem Biol 16, 1314–1320 (2020). https://doi.org/10.1038/s41589-020-0644-4

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