Differential actions of Pacific ciguatoxin-1 on sodium channel subtypes inmammalian sensory neurons

Pacific ciguatoxin-l (P-CTX-1), is a highly lipophilic cyclic polyether mol ecule originating from the marine dinoflagellate Gambierdiscus toxicus. Its effects were investigated on sodium channel subtypes present in acutely di ssociated rat dorsal root ganglion neurons, using whole-cell patch clamp te chniques. 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-resistan t (TTX-R) sodium channel activation and inactivation, however, a concentrat ion-dependent reduction in peak current amplitude occurred in both channel types. The main actions of 5 nM P-CTX-I on TTX-S sodium channels were a 13- mV hyperpolarizing shift in the voltage dependence of sodium channel activa tion and a 22-mV hyperpolarizing shift in steady-state inactivation (h(infi nity)). In addition, P-CTX-1 caused a rapid rise in the membrane leakage cu rrent in cells expressing TTX-S sodium channels. This effect was blocked by 200 nM TTX, indicating an action mediated through TTX-S sodium channels. I n 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 inactiva tion. These results indicate that P-CTX-1 acts to modify voltage-gated sodi um channels present in peripheral sensory neurons consistent with its actio n to increase nerve excitability. This provides an explanation for the sens ory neurological disturbances associated with ciguatera fish poisoning.