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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.

Original publication

DOI

10.1074/jbc.M112.441246

Type

Journal article

Journal

J Biol Chem

Publication Date

31/05/2013

Volume

288

Pages

16017 - 16030

Keywords

Calcium, Calcium Intracellular Release, NAADP, Ryanodine Receptor, Signal Transduction, Adrenergic beta-Agonists, Animals, Arrhythmias, Cardiac, Calcium Signaling, Cells, Cultured, Isoproterenol, Mice, Myocardium, Myocytes, Cardiac, NADP, Nicotinic Acids, Ryanodine Receptor Calcium Release Channel, Sarcoplasmic Reticulum