Journal of Biological Chemistry 2013-05-31

Nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated calcium signaling and arrhythmias in the heart evoked by β-adrenergic stimulation.

Merle Nebel, Alexander P Schwoerer, Dominik Warszta, Cornelia C Siebrands, Ann-Christin Limbrock, Joanna M Swarbrick, Ralf Fliegert, Karin Weber, Sören Bruhn, Martin Hohenegger, Anne Geisler, Lena Herich, Susan Schlegel, Lucie Carrier, Thomas Eschenhagen, Barry V L Potter, Heimo Ehmke, Andreas H Guse

Index: J. Biol. Chem. 288(22) , 16017-30, (2013)

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Abstract

Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca(2+)-releasing second messenger known to date. Here, we report a new role for NAADP in arrhythmogenic Ca(2+) release in cardiac myocytes evoked by β-adrenergic stimulation. Infusion of NAADP into intact cardiac myocytes induced global Ca(2+) signals sensitive to inhibitors of both acidic Ca(2+) stores and ryanodine receptors and to NAADP antagonist BZ194. Furthermore, in electrically paced cardiac myocytes BZ194 blocked spontaneous diastolic Ca(2+) transients caused by high concentrations of the β-adrenergic agonist isoproterenol. Ca(2+) transients were recorded both as increases of the free cytosolic Ca(2+) concentration and as decreases of the sarcoplasmic luminal Ca(2+) concentration. Importantly, NAADP antagonist BZ194 largely ameliorated isoproterenol-induced arrhythmias in awake mice. We provide strong evidence that NAADP-mediated modulation of couplon activity plays a role for triggering spontaneous diastolic Ca(2+) transients in isolated cardiac myocytes and arrhythmias in the intact animal. Thus, NAADP signaling appears an attractive novel target for antiarrhythmic therapy.