Differential actions of pacific ciguatoxin-1 on sodium channel subtypes in mammalian sensory neurons
1999
Strachan, Liesl C. | Lewis, Richard J. | Nicholson, Graham M.
Pacific ciguatoxin-1 (P-CTX-1), is a highly lipophilic cyclic polyether molecule originating from the marine dinoflagellateGambierdiscus toxicus. Its effects were investigated on sodium channel subtypes present in acutely dissociated rat dorsal root ganglion neurons, using whole-cell patch clamp techniques. Concentrations of P-CTX-1 ranging from 0.2 to 20 nM had no effect on the kinetics of tetrodotoxin-sensitive (TTX-S) or tetrodotoxin-resistant (TTX-R) sodium channel activation and inactivation, however, a concentration-dependent reduction in peak current amplitude occurred in both channel types. The main actions of 5 nM P-CTX-1 on TTX-S sodium channels were a 13-mV hyperpolarizing shift in the voltage dependence of sodium channel activation and a 22-mV hyperpolarizing shift in steady-state inactivation (h∞). In addition, P-CTX-1 caused a rapid rise in the membrane leakage current in cells expressing TTX-S sodium channels. This effect was blocked by 200 nM TTX, indicating an action mediated through TTX-S sodium channels. In contrast, the main action of P-CTX-1 (5 nM) on TTX-R sodium channels was a significant increase in the rate of recovery from sodium channel inactivation. These results indicate that P-CTX-1 acts to modify voltage-gated sodium channels present in peripheral sensory neurons consistent with its action to increase nerve excitability. This provides an explanation for the sensory neurological disturbances associated with ciguatera fish poisoning.
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