A study on mechanisms of toxic actions of ciguatoxins: existence of functional relationship between CTX3C and charged residues of voltage sensors in Nav1.4 sodium channel

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Ciguatoxins, a group of virulent marine toxins, are bound to "site 5" inside voltage-dependent sodium channels and alter their kinetics dramatically; this is probably responsible for clinical symptoms of ciguatoxin poisoning or ciguatera. Although ciguatoxins are known to affect the voltage dependency of both activation and inactivation kinetics, site 5 has not been functionally clarified. This study, therefore, targeted putative voltage sensors as a receptor for ciguatoxins. We constructed mutants, in which 1 of 23 basic residues was substituted with glutamine in the S4 segment for each of four domains. We then examined the effects of a synthetic ciguatoxin congener CTX3C on these mutants. Notably, the suppressive effect of CTX3C on the sodium current (I Na) amplitude of domain 2 mutants, which carried a mutation in the basic S4 residue of domain 2, was either reduced or eliminated. Kinetic analyses of domain 2 mutants in comparison with those of the wild type and other mutants revealed that the negative shift of the steady-state inactivation curve (V 1/2inactΔ) was significantly decreased. The resistance of domain 2 mutants to CTX3C in terms of changes in V 1/2inact is suggested to be closely related to resistance to the suppressive effect of CTX3C on the I Na amplitude. This is the first report to demonstrate the existence of a functional relationship between a ciguatoxin congener and voltage sensor segments in domain 2 of the α-subunit of voltage-dependent sodium channels, although further studies are needed to locate a ciguatoxin receptor.