Recent advances in the study of mechanism of action of marine neurotoxins

Abstract

A variety of marine neurotoxins exert potent and specific actions on neuronal sodium channels. Tetrodotoxin and saxitoxin block the sodium channel selectively without any effect on other types of voltage-activated and transmitter-activated ion channels. They bind to a site near the external orifice of the sodium channel on a one-to-one stoichiometric basis. The block is influenced by the membrane potential in a complex manner, and binding and penetration of calcium ions to the sodium channel appear to be responsible for the voltage-dependent block. Owing to the potent and specific sodium channel blocking action, tetrodotoxin and saxitoxin have been used extensively in various studies of ion channels. The dorsal root ganglion neurons of the rat are endowed with tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels. The latter is also resistant to saxitoxin. These two types of sodium channels exhibit different physiological and pharmacological profiles. Tetrodotoxin-resistant sodium channels are slower in time course and open and inactivate at less negative membrane potentials than tetrodotoxin-sensitive sodium channels. Lidocaine blocks tetrodotoxin-sensitive sodium channels more potently than tetrodotoxin-resistant sodium channels. However, Pb2+ and Cd2+ block tetrodotoxin-resistant channels more strongly. The pyrethroid insecticide allethrin modifies tetrodotoxin-resistant sodium channels while affecting tetrodotoxin-sensitive sodium channels to a much lesser extent. The differences in pharmacological and toxicological profiles between the two types of sodium channels are deemed critically important in understanding the mechanisms of action of various chemicals in animals.