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

doi:10.1074/jbc.274.25.17820

Stevan Rakovic, Yi Cui + Show 5 more

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https://doi.org/10.1074/jbc.274.25.17820

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Abstract

Oscillations of Ca2+ in heart cells are a major underlying cause of important cardiac arrhythmias, and it is known that Ca2+-induced release of Ca2+ 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 Ca2+ release channel of the sarcoplasmic reticulum (the ryanodine receptor), raising the possibility that cADP-ribose may influence arrhythmogenic mechanisms in the heart. 8-Amino-cADP-ribose, an antagonist of cADP-ribose, suppressed oscillatory activity associated with overloading of intracellular Ca2+ stores in cardiac myocytes exposed to high doses of the beta-adrenoreceptor agonist isoproterenol or the Na+/K+-ATPase inhibitor ouabain. The oscillations suppressed by 8-amino-cADP-ribose included intracellular Ca2+ 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 cADP-ribose concentration is present within the cell, we propose that 8-amino-cADP-ribose and 8-bromo-cADP-ribose suppress cytosolic Ca2+ oscillations by antagonism of endogenous cADP-ribose, which sensitizes the Ca2+ release channels of the sarcoplasmic reticulum to Ca2+.

Highlights

Oscillations of Ca2؉ in heart cells are a major underlying cause of important cardiac arrhythmias, and it is known that Ca2؉-induced release of Ca2؉ from intracellular stores is fundamental to the generation of such oscillations
The above data demonstrate a suppressive effect of 8-aminocADPR and 8-bromo-cADPR on spontaneous Ca2ϩ waves, contractions, and electrical activity recorded in guinea pig ventricular myocytes under conditions of Ca2ϩ overload induced by isoproterenol or ouabain
We have reported previously that, in guinea pig ventricular myocytes stimulated to fire action potentials at 1 Hz, injection of 8-amino-cADPR reduces the Ca2ϩ transient and accompanying contraction by a mechanism involving a decrease in the quantity of Ca2ϩ released from the sarcoplasmic reticulum (SR) but with no reduction in the amount of stored Ca2ϩ [13]

Summary

Introduction

Oscillations of Ca2؉ in heart cells are a major underlying cause of important cardiac arrhythmias, and it is known that Ca2؉-induced release of Ca2؉ from intracellular stores (the sarcoplasmic reticulum) is fundamental to the generation of such oscillations. Within 3 min of 8-amino-cADPR injection, spontaneous electrical activity was completely abolished in this cell, whereas the generation of stimulated action potentials was not affected.

Results

Conclusion