Tetrodotoxin, saxitoxin, chiriquitoxin: new perspectives on ionic channels.

Chiriquitoxin is a new, natural analog of tetrodotoxin, differing only in having the -CH2OH on C-6 replaced with an unidentified group of 104 mass units. On isolated frog sartorius muscle fibers, chiriquitoxin is equipotent with tetrodotoxin in blocking the Na+ channel, as shown by their identical dose-response relations on the maximum rate of rise of the action potential. Chiriquitoxin additionally interferes with some K+ channels, as shown by a slowed repolarization of the action potential, a reduced steady-state membrane conductance in current-clamped fibers, and a reduced K+ current in point-voltage-clamped fibers. The effects of chiriquitoxin on the Na+ and K+ channels are apparently exerted by the same molecule because high concentration of tetrodotoxin can either prevent or reverse the effects of chiriquitoxin on the K+ channel. Therefore, the receptor for tetrodotoxin-chiriquitoxin is probably not located inside the Na+ channel, but is on the outside surface of the membrane close to the orifice of the Na+ channel. The results also suggest that the Na+ and K+ channels are probably not randomly distributed throughout the membrane, but occur in clusters with some definite spatial relation to each other. From the structure of tetrodotoxin and a presumed structure of chiriquitoxin, the Na+ and K+ channels are estimated to be separated from each other by not less than 5 nor much more than 15A. The receptor for saxitoxin may be different, but partially overlapping with that for tetrodotoxin-chiriquitoxin.