An Antagonist of cADP-ribose Inhibits Arrhythmogenic Oscillations of Intracellular Ca2+In Heart Cells

Stevan Rakovic, Yi Cui, Shigeo Iino, Antony Galione, Gloria A. Ashamu, Barry V. L. Potter, Derek A. Terrar
1999 Journal of Biological Chemistry  
Oscillations of Ca 2؉ in heart cells are a major underlying cause of important cardiac arrhythmias, and it is known that Ca 2؉ -induced release of Ca 2؉ from intracellular stores (the sarcoplasmic reticulum) is fundamental to the generation of such oscillations. There is now evidence that cADP-ribose may be an endogenous regulator of the Ca 2؉ release channel of the sarcoplasmic reticulum (the ryanodine receptor), raising the possibility that cADP-ribose may influence arrhythmogenic mechanisms
more » ... n the heart. 8-Amino-cADP-ribose, an antagonist of cADP-ribose, suppressed oscillatory activity associated with overloading of intracellular Ca 2؉ stores in cardiac myocytes exposed to high doses of the ␤-adrenoreceptor agonist isoproterenol or the Na ؉ /K ؉ -ATPase inhibitor ouabain. The oscillations suppressed by 8-amino-cADP-ribose included intracellular Ca 2؉ waves, spontaneous action potentials, after-depolarizations, and transient inward currents. Another antagonist of cADP-ribose, 8-bromo-cADP-ribose, was also effective in suppressing isoproterenol-induced oscillatory activity. Furthermore, in the presence of ouabain under conditions in which there was no arrhythmogenesis, exogenous cADP-ribose was found to be capable of triggering spontaneous contractile and electrical activity. Because enzymatic machinery for regulating the cytosolic cADPribose concentration is present within the cell, we propose that 8-amino-cADP-ribose and 8-bromo-cADP-ribose suppress cytosolic Ca 2؉ oscillations by antagonism of endogenous cADP-ribose, which sensitizes the Ca 2؉ release channels of the sarcoplasmic reticulum to Ca 2؉ .
doi:10.1074/jbc.274.25.17820 pmid:10364226 fatcat:jhvbgvgq45cpxfg3qmef5egdty