TY - JOUR
T1 - Multiple sodium channel isoforms mediate the pathological effects of Pacific ciguatoxin-1
AU - Inserra, Carco
AU - Israel, Mathilde
AU - Caldwell, Ashlee
AU - Castro, Joel
AU - Deuis, Jennifer
AU - Harrington, Andrea
AU - Keramidas, Angelo
AU - Garcia-Caraballo, Sonia
AU - Maddern, Jessica
AU - Erickson, Andelain
AU - Grundy, Luke
AU - Rychkov, Grigori
AU - Zimmermann, Katharina
AU - Lewis, Richard
AU - Brierley, Stuart
AU - Vetter, Irina
PY - 2017/2/22
Y1 - 2017/2/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85013892011&partnerID=8YFLogxK
U2 - 10.1038/srep42810
DO - 10.1038/srep42810
M3 - Article
VL - 7
SP - Art: 42810
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 42810
ER -