title: Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1.
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 NaVtoxin and shifted the voltage-dependence of activation to more hyperpolarising potentials at all NaVsubtypes, 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 NaVisoforms in peripheral sensory neurons and their contribution to membrane depolarisation, action potential initiation and propagation.
authors.affiliation: Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, 306 Carmody Rd, St Lucia, Queensland 4072, Australia.
authors.forename: Marco C
authors.initials: MC
authors.lastname: Inserra
authors.affiliation: Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, 306 Carmody Rd, St Lucia, Queensland 4072, Australia.
authors.forename: Mathilde R
authors.initials: MR
authors.lastname: Israel
authors.affiliation: Visceral Pain Group, South Australian Health and Medical Research Institute (SAHMRI), School of Medicine, Flinders University, Adelaide, South Australia 5000, Australia.|Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia 5000, Australia.
authors.forename: Ashlee
authors.initials: A
authors.lastname: Caldwell
authors.affiliation: Visceral Pain Group, South Australian Health and Medical Research Institute (SAHMRI), School of Medicine, Flinders University, Adelaide, South Australia 5000, Australia.|Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia 5000, Australia.
authors.forename: Joel
authors.initials: J
authors.lastname: Castro
authors.affiliation: Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, 306 Carmody Rd, St Lucia, Queensland 4072, Australia.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Deuis
authors.affiliation: Visceral Pain Group, South Australian Health and Medical Research Institute (SAHMRI), School of Medicine, Flinders University, Adelaide, South Australia 5000, Australia.|Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia 5000, Australia.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Harrington
authors.affiliation: Queensland Brain Institute, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: Angelo
authors.initials: A
authors.lastname: Keramidas
authors.affiliation: Visceral Pain Group, South Australian Health and Medical Research Institute (SAHMRI), School of Medicine, Flinders University, Adelaide, South Australia 5000, Australia.|Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia 5000, Australia.
authors.forename: Sonia
authors.initials: S
authors.lastname: Garcia-Caraballo
authors.affiliation: Visceral Pain Group, South Australian Health and Medical Research Institute (SAHMRI), School of Medicine, Flinders University, Adelaide, South Australia 5000, Australia.|Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia 5000, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Maddern
authors.affiliation: Visceral Pain Group, South Australian Health and Medical Research Institute (SAHMRI), School of Medicine, Flinders University, Adelaide, South Australia 5000, Australia.|Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia 5000, Australia.
authors.forename: Andelain
authors.initials: A
authors.lastname: Erickson
authors.affiliation: Visceral Pain Group, South Australian Health and Medical Research Institute (SAHMRI), School of Medicine, Flinders University, Adelaide, South Australia 5000, Australia.|Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia 5000, Australia.
authors.forename: Luke
authors.initials: L
authors.lastname: Grundy
authors.affiliation: Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia 5000, Australia.
authors.forename: Grigori Y
authors.initials: GY
authors.lastname: Rychkov
authors.affiliation: Klinik für Anästhesiologie am Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Zimmermann
authors.affiliation: Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, 306 Carmody Rd, St Lucia, Queensland 4072, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lewis
authors.affiliation: Visceral Pain Group, South Australian Health and Medical Research Institute (SAHMRI), School of Medicine, Flinders University, Adelaide, South Australia 5000, Australia.|Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia 5000, Australia.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Brierley
authors.affiliation: Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, 306 Carmody Rd, St Lucia, Queensland 4072, Australia.|School of Pharmacy, The University of Queensland, 20 Cornwall St, Woolloongabba, Queensland 4102, Australia.
authors.forename: Irina
authors.initials: I
authors.lastname: Vetter
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002478:Cells, Cultured; D002922:Ciguatoxins / Q000633:toxicity*; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D020033:Protein Isoforms / Q000378:metabolism; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D061566:Voltage-Gated Sodium Channels; D002922:Ciguatoxins