Palytoxin disrupts cardiac excitation-contraction coupling through interactions with P-type ion pumps.
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(2+) concentration ([Ca(2+)](i)), a decrease in [Ca(2+)](i) transient amplitude, Ca(2+) alternans followed by [Ca(2+)](i) waves, and failures of Ca(2+) release. The decrease in [Ca(2+)](i) transient amplitude occurred despite high sarcoplasmic reticulum (SR) Ca(2+) load. In voltage-clamped myocytes, palytoxin induced a current with a linear current-voltage relationship (reversal potential approximately 5 mV) that was blocked by ouabain. Whole cell Ca(2+) current and ryanodine receptor Ca(2+) release channel function remained unaffected by the toxin. However, palytoxin significantly reduced Ca(2+) pumping of isolated SR vesicles. In current-clamped 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(+)-K(+) pump and the SR Ca(2+) pump. The suggested mode of palytoxin toxicity in the atrium involves the conversion of Na(+)-K(+) pumps into nonselective cation channels as a primary event followed by depolarization, Na(+) accumulation, and Ca(2+) overload, which, in turn, causes arrhythmogenic [Ca(2+)](i) waves and delayed afterdepolarizations.
Kockskämper
Jens
J
Department of Physiology, Loyola University-Chicago, 2160 S. First Avenue, Maywood, IL 60153, USA.
Ahmmed
Gias U
GU
Zima
Aleksey V
AV
Sheehan
Katherine A
KA
Glitsch
Helfried G
HG
Blatter
Lothar A
LA
D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology; D002415:Cats; D003064:Cnidarian Venoms; D004558:Electric Stimulation; D006325:Heart Atria / Q000166:cytology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D010042:Ouabain / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D000095702:Polyether Toxins
D000178:Acrylamides; D002118:Calcium; D000252:Calcium-Transporting ATPases; D002316:Cardiotonic Agents; D003064:Cnidarian Venoms; D010042:Ouabain; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase; C010272:palytoxin; D000095702:Polyether Toxins