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A naturally occurring amino acid substitution in the voltage-dependent sodium channel selectivity filter affects channel gating

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Abstract

The pore of sodium channels contains a selectivity filter made of 4 amino acids, D/E/K/A. In voltage sensitive sodium channel (Nav) channels from jellyfish to human the fourth amino acid is Ala. This Ala, when mutated to Asp, promotes slow inactivation. In some Nav channels of pufferfishes, the Ala is replaced with Gly. We studied the biophysical properties of an Ala-to-Gly substitution (A1529G) in rat Nav1.4 channel expressed in Xenopus oocytes alone or with a β1 subunit. The Ala-to-Gly substitution does not affect monovalent cation selectivity and positively shifts the voltage-dependent inactivation curve, although co-expression with a β1 subunit eliminates the difference between A1529G and WT. There is almost no difference in channel fast inactivation, but the β1 subunit accelerates WT current inactivation significantly more than it does the A1529G channels. The Ala-to-Gly substitution mainly influences the rate of recovery from slow inactivation. Again, the β1 subunit is less effective on speeding recovery of A1529G than the WT. We searched Nav channels in numerous databases and noted at least four other independent Ala-to-Gly substitutions in Nav channels in teleost fishes. Thus, the Ala-to-Gly substitution occurs more frequently than previously realized, possibly under selection for alterations of channel gating.

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Acknowledgments

This work was supported by National Institutes of Health Grant R01GM084879 and a Wellcome Trust/DBT Early Career fellowship to BS. We thank Drs. Harry Fozzard, Jack Kyle and Alan Goldin for all constructs used in the work. We also thank Dr. Adron Harris for providing the facility for oocyte work.

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Authors and Affiliations

  1. Section of Neurobiology, Institute for Neuroscience, University of Texas at Austin, Austin, TX, 78712, USA

    Mingming Wu, Na Ye & Harold H. Zakon

  2. The Wellcome Trust Centre for Neuroimaging, University College London, London, UK

    Biswa Sengupta

  3. Centre for Neuroscience, Indian Institute of Science, Bangalore, India

    Biswa Sengupta

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  1. Mingming Wu
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  2. Na Ye
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  4. Harold H. Zakon
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Correspondence to Mingming Wu.

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Wu, M., Ye, N., Sengupta, B. et al. A naturally occurring amino acid substitution in the voltage-dependent sodium channel selectivity filter affects channel gating. J Comp Physiol A 199, 829–842 (2013). https://doi.org/10.1007/s00359-013-0845-3

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