The Na+/K+ ATPase inhibitor Palytoxin acts by:
Palytoxin ranks among most potent non-protein toxins known, isolated from zoanthid corals Palythoa species, with LD50 subnanomolar due to profound effects on ion homeostasis. Target is Na+/K+ ATPase, P-type pump normally undergoing strict alternating access never simultaneously open both sides. Structural and electrophysiological studies show palytoxin binds extracellular entrance near ouabain site but wedges gates open, stabilizing conformation where intracellular gate formed by M5-M8 and extracellular gate formed by M1-M4 both unlatched, generating continuous pore approximately 13 angstrom diameter spanning membrane. Electrophysiology reveals large non-selective conductance allowing sodium, potassium, lithium, even organic cations like choline and tetramethylammonium to flow passively down gradients, collapsing resting potential causing depolarization, secondary calcium overload via reverse sodium calcium exchange, ATP depletion. Pump cycling halted ATP hydrolysis blocked because enzyme arrested unable to complete E1-E2 transition, but functional outcome differs from simple inhibition by ouabain that blocks without creating channel. Thus palytoxin action defined as converting pump into non-specific ion channel.
Ref: Tosteson et al., Palytoxin Converts Na+/K+ ATPase into Non-Selective Ion Channel Mechanism.