Palytoxin action on the Na+,K+-ATPase and the disruption of ion equilibria in biological systems

Palytoxin-group toxins (PlTX) exert their potent biological activity by altering mechanisms of ion homeostasis in excitable and non-excitable tissues. This review will describe major aspects that led to the relatively early identification of the Na+,K+-ATPase as the molecular target and receptor of the toxin in sensitive systems. The importance of this pump in the normal functioning of animal cells has driven extensive investigative efforts. The recognized molecular mechanism of action of PlTX involves its binding to the extracellular portion of alpha subunits of this plasma membrane protein, which converts an enzyme carrying ions against their concentration gradient at the expense of chemical energy (ATP) into a non-selective cation channel, allowing passive flow of ions following their concentration gradients. More recent findings have indicated that PlTX would interfere with the normal strict coupling between inner and outer gates of the pump controlling the ion access to the Na+,K+-ATPase, allowing the gates to be simultaneously open. The ability of PlTX to make internal portions of the Na+,K+-ATPase accessible to relatively large molecules has been exploited to characterize the structure-function relationship of the pump, leading to a better understanding of its ion translocation pathway. Thus, forty years from the isolation of this potent marine biotoxin, a considerable understanding of its mode of action and of its potential as a research tool have been achieved and are the basis for promising future advancement in the characterization of biological systems and their alteration by PlTX.