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Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1
Inserra, M.C.; Israel, M.R.; Caldwell, A.; Castro, J.; Deuis, J.R.; Harrington, A.M.; Keramidas, A.; Garcia-Caraballo, S.; Maddern, J.; Erickson, A.; Grundy, L.; Rychkov, G.Y.; Zimmermann, K.; Lewis, R.J.; Brierley, S.M.; Vetter, I. (2017). Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1. NPG Scientific Reports 7: 42810. https://dx.doi.org/10.1038/srep42810
In: Scientific Reports (Nature Publishing Group). Nature Publishing Group: London. ISSN 2045-2322; e-ISSN 2045-2322, meer
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  • Inserra, M.C.
  • Israel, M.R.
  • Caldwell, A.
  • Castro, J.
  • Deuis, J.R.
  • Harrington, A.M.
  • Keramidas, A.
  • Garcia-Caraballo, S.
  • Maddern, J.
  • Erickson, A.
  • Grundy, L.
  • Rychkov, G.Y.
  • Zimmermann, K.
  • Lewis, R.J.
  • Brierley, S.M.
  • Vetter, I., meer
Abstract
    Human intoxication with the seafood poison ciguatoxin, a dinoflagellate polyether that activates voltage-gated sodium channels (NaV), 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 NaV1.1–1.9 using imaging and electrophysiological approaches. Although P-CTX-1 is essentially a non-selective NaV toxin and shifted the voltage-dependence of activation to more hyperpolarising potentials at all NaV subtypes, an increase in the inactivation time constant was observed only at NaV1.8, while the slope factor of the conductance-voltage curves was significantly increased for NaV1.7 and peak current was significantly increased for NaV1.6. Accordingly, P-CTX-1-induced visceral and cutaneous pain behaviours were significantly decreased after pharmacological inhibition of NaV1.8 and the tetrodotoxin-sensitive isoforms NaV1.7 and NaV1.6, 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 NaV isoforms in peripheral sensory neurons and their contribution to membrane depolarisation, action potential initiation and propagation.
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