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

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

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    31 Citations (Scopus)

    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
    Pages (from-to)Art: 42810
    Number of pages19
    JournalScientific Reports
    Volume7
    DOIs
    Publication statusPublished - 2017

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  • Cite this

    Inserra, C., Israel, M., Caldwell, A., Castro, J., Deuis, J., Harrington, A., Keramidas, A., Garcia-Caraballo, S., Maddern, J., Erickson, A., Grundy, L., Rychkov, G., Zimmermann, K., Lewis, R., Brierley, S., & Vetter, I. (2017). Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1. Scientific Reports, 7, Art: 42810. [42810]. https://doi.org/10.1038/srep42810