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A quantitative and comparative study of the effects of a synthetic ciguatoxin CTX3C on the kinetic properties of voltage‐dependent sodium channels
Author(s) -
Yamaoka Kaoru,
Inoue Masayuki,
Miyahara Hidemichi,
Miyazaki Keisuke,
Hirama Masahiro
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705852
Subject(s) - sodium channel , chemistry , gene isoform , ciguatoxin , biophysics , toxin , membrane potential , sodium , biochemistry , biology , organic chemistry , fishery , fish <actinopterygii> , gene
Ciguatoxins (CTXs) are known to bind to receptor site 5 of the voltage‐dependent Na channel, but the toxin's physiological effects are poorly understood. In this study, we investigated the effects of a ciguatoxin congener (CTX3C) on three different Na‐channel isoforms, rNa v 1.2, rNa v 1.4, and rNa v 1.5, which were transiently expressed in HEK293 cells. The toxin (1.0 μ mol l −1 ) shifted the activation potential ( V 1/2 of activation curve) in the negative direction by 4–9 mV and increased the slope factor ( k ) from 8 mV to between 9 and 12 mV (indicative of decreased steepness of the activation curve), thereby resulting in a hyperpolarizing shift of the threshold potential by 30 mV for all Na channel isoforms. The toxin (1.0 μ mol l −1 ) significantly accelerated the time‐to‐peak current from 0.62 to 0.52 ms in isoform rNa v 1.2. Higher doses of the toxin (3–10 μ mol l −1 ) additionally decreased time‐to‐peak current in rNa v 1.4 and rNa v 1.5. A toxin effect on decay of I Na at −20 mV was either absent or marginal even at relatively high doses of CTX3C. The toxin (1 μ mol l −1 ) shifted the inactivation potential ( V 1/2 of inactivation curve) in the negative direction by 15–18 mV in all isoforms.I Na maxima of the I – V curve (at −20 mV) were suppressed by application of 1.0 μ mol l −1 CTX3C to a similar extent (80–85% of the control) in all the three isoforms. Higher doses of CTX3C up to 10 μ mol l −1 further suppressed I Na to 61–72% of the control. Recovery from slow inactivation induced by a depolarizing prepulse of intermediate duration (500 ms) was dramatically delayed in the presence of 1.0 μ mol l −1 CTX3C, as time constants describing the monoexponential recovery were increased from 38±8 to 588±151 ms ( n =5), 53±6 to 338±85 ms ( n =4), and 23±3 to 232±117 ms ( n =3) in rNa v 1.2, rNa v 1.4, and rNa v 1.5, respectively. CTX3C exerted multimodal effects on sodium channels, with simultaneous stimulatory and inhibitory aspects, probably due to the large molecular size (3 nm in length) and lipophilicity of this membrane‐spanning toxin.British Journal of Pharmacology (2004) 142 , 879–889. doi: 10.1038/sj.bjp.0705852