The cardiac acetylcholine-activated, inwardly rectifying K+-channel subunit GIRK1 gives rise to an inward current induced by free oxygen radicals

Reactive oxygen species (ROS) play a crucial role in pathophysiology of the cardiovascular system. The present study was designed to analyze the redox sensitivity of G-protein-activated inward rectifier K+ (GIRK) channels, wh ich control cardiac contractility and excitability, GIRK1 subunits were het erologously expressed in Xenopus laevis oocytes and the resulting K+ curren ts were measured with the two-electrode voltage clamp technique. Oxygen fre e radicals generated by the hypoxanthine/xanthine oxidase system led to a m arked increase in the current through GIRK channels, termed superoxide-indu ced current (I-SO). Furthermore, I-SO did not depend on G-protein-dependent activation of GIRK currents by coexpressed muscarinic m(2)-receptors, but could also be observed when no agonist was present in the bathing solution. Niflumic acid at a concentration of 0.5 mmol/l did not abolish I-SO, where as 100 mu mol/l Ba2+ attenuated I-SO completely. Catalase (10(6) i.u./l) fa iled to suppress I-SO, whereas H2O2 concentration was kept close to zero, a s measured by chemiluminescence. Hence, we conclude that O-2(.-) or a close ly related species is responsible for I-SO induction. Our results demonstra te a significant redox sensitivity of GIRK1 channels and suggest redox-acti vation of G-protein-activated inward rectifier K+ channels as a key mechani sm in oxidative stress-associated cardiac dysfunction. (C) 1998 Elsevier Sc ience Inc.