Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1

Marco C. Inserra, Mathilde R. Israel, Ashlee Caldwell, Joel Castro, Jennifer R. Deuis, Andrea M. Harrington, Angelo Keramidas, Sonia Garcia-Caraballo, Jessica Maddern, Andelain Erickson, Luke Grundy, Grigori Y. Rychkov, Katharina Zimmermann, Richard J. Lewis, Stuart M. Brierley, Irina Vetter

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Abstract

Human intoxication with the seafood poison ciguatoxin, a dinoflagellate polyether that activates voltage-gated sodium channels (Na V), causes ciguatera, a disease characterised by gastrointestinal and neurological disturbances. We assessed the activity of the most potent congener, Pacific ciguatoxin-1 (P-CTX-1), on Na V 1.1-1.9 using imaging and electrophysiological approaches. Although P-CTX-1 is essentially a non-selective Na V toxin and shifted the voltage-dependence of activation to more hyperpolarising potentials at all Na V subtypes, an increase in the inactivation time constant was observed only at Na V 1.8, while the slope factor of the conductance-voltage curves was significantly increased for Na V 1.7 and peak current was significantly increased for Na V 1.6. Accordingly, P-CTX-1-induced visceral and cutaneous pain behaviours were significantly decreased after pharmacological inhibition of Na V 1.8 and the tetrodotoxin-sensitive isoforms Na V 1.7 and Na V 1.6, respectively. The contribution of these isoforms to excitability of peripheral C- and A-fibre sensory neurons, confirmed using murine skin and visceral single-fibre recordings, reflects the expression pattern of Na V isoforms in peripheral sensory neurons and their contribution to membrane depolarisation, action potential initiation and propagation.

Original languageEnglish
Article number42810
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 22 Feb 2017

ASJC Scopus subject areas

  • General

Cite this

Inserra, M. C., Israel, M. R., Caldwell, A., Castro, J., Deuis, J. R., Harrington, A. M., ... Vetter, I. (2017). Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1. Scientific Reports, 7, [42810]. https://doi.org/10.1038/srep42810