Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP)-mediated Calcium Signaling and Arrhythmias in the Heart Evoked by beta-Adrenergic Stimulation

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

来源：Journal of Biological Chemistry, 2013, 288(22): 16017-16030.

DOI：10.1074/jbc.M112.441246

Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+-releasing second messenger known to date. Here, we report a new role for NAADP in arrhythmogenic Ca2+ release in cardiac myocytes evoked by beta-adrenergic stimulation. Infusion of NAADP into intact cardiac myocytes induced global Ca2+ signals sensitive to inhibitors of both acidic Ca2+ stores and ryanodine receptors and to NAADP antagonist BZ194. Furthermore, in electrically paced cardiac myocytes BZ194 blocked spontaneous diastolic Ca2+ transients caused by high concentrations of the beta-adrenergic agonist isoproterenol. Ca2+ transients were recorded both as increases of the free cytosolic Ca2+ concentration and as decreases of the sarcoplasmic luminal Ca2+ 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 Ca2+ transients in isolated cardiac myocytes and arrhythmias in the intact animal. Thus, NAADP signaling appears an attractive novel target for antiarrhythmic therapy.

• 出版日期2013-5-31