Palytoxin disrupts cardiac excitation-contraction coupling through interactions with P-type ion pumps

Abstract

Palytoxin is a coral toxin that seriously impairs heart function, but its effects on excitation-contraction (E-C) coupling have remained elusive. Therefore, we studied the effects of palytoxin on mechanisms involved in atrial E-C coupling. In field-stimulated cat atrial myocytes, palytoxin caused elevation of diastolic intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i), a decrease in [Ca 2ϩ ]i transient amplitude, Ca 2ϩ alternans followed by [Ca 2ϩ ]i waves, and failures of Ca 2ϩ release. The decrease in [Ca 2ϩ ]i transient amplitude occurred despite high sarcoplasmic reticulum (SR) Ca 2ϩ load. In voltage-clamped myocytes, palytoxin induced a current with a linear current-voltage relationship (reversal potential ϳ5 mV) that was blocked by ouabain. Whole cell Ca 2ϩ current and ryanodine receptor Ca 2ϩ release channel function remained unaffected by the toxin. However, palytoxin significantly reduced Ca 2ϩ pumping of isolated SR vesicles. In currentclamped myocytes stimulated at 1 Hz, palytoxin induced a depolarization of the resting membrane potential that was accompanied by delayed afterdepolarizations. No major changes of action potential configuration were observed. The results demonstrate that palytoxin interferes with the function of the sarcolemmal Na ϩ -K ϩ pump and the SR Ca 2ϩ pump. The suggested mode of palytoxin toxicity in the atrium involves the conversion of Na ϩ -K ϩ pumps into nonselective cation channels as a primary event followed by depolarization, Na ϩ accumulation, and Ca 2ϩ overload, which, in turn, causes arrhythmogenic [Ca 2ϩ ]i waves and delayed afterdepolarizations. atrial myocytes; intracellular calcium PALYTOXIN IS A NONPEPTIDE TOXIN with a unique chemical structure isolated from corals of the genus Palythoa (34). It is the most potent animal toxin known to date (14, 50). Palytoxin intoxication leads to severe vasoconstriction, depression of cardiac function (25, 50), and, possibly, myocardial damage (36). At the cellular level, the toxin causes Na ϩ influx and K ϩ efflux, accompanied by depolarization, in all mammalian cell types studied (14). Cardiac glycosides (cymarin, ouabain, and digitoxin), specific inhibitors of the Na ϩ -K ϩ pump (Na ϩ -K ϩ -ATPase), can partially or fully antagonize the actions of palytoxin, pointing to the Na ϩ -K ϩ pump as the molecular target of the toxin (14). Nevertheless, several other modes of action have been proposed (10). Recent studies of yeast cells expressing mammalian Na ϩ -K ϩ pumps (39, 46) and of isolated Na ϩ -K ϩ pumps incorporated into planar lipid bilayers (18, 26), however, have shown unambiguously that palytoxin indeed targets the Na ϩ -K ϩ pump, converting the enzyme into a nonselective cation channel (summarized in Ref. 44). Furthermore, elegant kinetic studies of palytoxin-induced channels in cardiac myocytes and HEK-293 cells strongly support the notion that the toxin binds to the pump molecule and locks it in a channel-like open state (2).In the heart, palytoxin leads to myocardial ischemia, ventricular fibrillation, and cardiac fa...

Effects of Sodium Pump Activity on Spontaneous Firing in Neurons of the Rat Suprachiasmatic Nucleus

“…Palytoxin transforms the sodium pump into a nonselective cation channel and has been shown to increase firing in various tissues (Frelin and van Renterghem 1995;Kockskämper et al 2004;Sheridan et al 2005). This is also the case for SCN neurons as recorded with both cell-attached and whole cell modes (Fig.…”

A roadmap for hazard monitoring and risk assessment of marine biotoxins on the basis of chemical and biological test systems

“…Indeed, Artigas and Gadsby demonstrated that Pltx and ouabain can simultaneously bind to Na + /K + -AtPase (Artigas and Gadsby, 2004), suggesting the possibility of two different binding sites on the pump, as also confirmed by Pelin and colleagues (Pelin et al, 2013a). Pltx toxins were also shown to affect other membrane ion transport components (Frelin and Van Renterghem, 1995;Ikeda et al, 1988;Muramatsu et al, 1984;Sauviat, 1989;Kockskamper et al, 2004): the toxin could also interfere with other P-type AtPases such as the sarcoplasmic endoplasmatic reticulum Ca 2+ pump (SeRCA) (Coca et al, 2008;Kockskamper et al, 2004) and the non-gastric Na + /K + AtPase pump (Qiu et al, 2006;Scheiner-Bobis et al, 2002).…”

“…Intracellular Na + accumulation induces the transport of Ca 2+ into the cells via Na + /Ca 2+ exchangers (Frelin and Van Renterghem, 1995;Ikeda et al, 1988;Kockskamper et al, 2004;Vale et al, 2006). the latter increased intracellular Ca 2+ concentration affects skeletal, heart and smooth muscle cells (Frelin and Van Renterghem, 1995;Ito et al, 1977;Karaki et al, 1988;Kockskamper et al, 2004;Nagase and Karaki, 1987;Vale et al, 2006).…”

“…the latter increased intracellular Ca 2+ concentration affects skeletal, heart and smooth muscle cells (Frelin and Van Renterghem, 1995;Ito et al, 1977;Karaki et al, 1988;Kockskamper et al, 2004;Nagase and Karaki, 1987;Vale et al, 2006).…”

Scientific Opinion on marine biotoxins in shellfish - Palytoxin group

“…As a consequence of the molecular action of PlTX skeletal, heart and smooth muscle cells are the major targets of PlTX among excitable cells, responding with contraction induced both directly, following the increased intracellular Ca 2+ concentrations (Ito et al, 1977;Frelin and Van Renterghem, 1995;Kockskämper et al, 2004), and indirectly, through the Ca 2+ -induced release of neurotransmitters (Nagase and Karaki, 1987;Karaki et al, 1988). …”