The effects of palytoxin (PTX) on transmembrane potentials and currents of frog skeletal muscle were analyzed by intracellular microelectrode techniques and the double sucrose-gap voltage clamp method. 2. PTX irreversibly depolarized the membrane. The depolarization was Na-sensitive. 3. Under voltage clamp, PTX induced an inward resting current which did not inactivate, was inhibited by external Na+ removal and was a function of external Na concentration. 4. This resting current could be carried either by Na+, Li+, K+ or by guanidinium according to the permeability sequence K+ less than Li+ less than Na+ less than Gua+. 5. The PTX-induced current was only weakly sensitive to tetrodotoxin. It was reversibly and dose-dependently inhibited by amiloride with a one to one stoichiometry and a KD of 0.3 mM. 6. Acidic pH partially inhibited the current induced by PTX which was also highly sensitive to external Cd2+ and La3+. The inhibitory sequence for divalent cations was: Mg2+ less than Ca2+ = Ba2+ = Mn2+ less than Cd2+; with La3+ greater than Cd2+. 7. The amplitude of the PTX-induced I(rest) was markedly reduced in the absence of external Ca2+. 8. PTX induced a Na+ resting conductance in frog skeletal muscle. The size of the channel induced by PTX is larger than the guanidinium ion. External membrane Ca2+ might be a cofactor involved in the mode of action of PTX.
