Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 22, Pages 16017-16030Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.441246
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Funding
- Deutsche Forschungsgemeinschaft [FOR-604-GU 360/10-1, GU 360/10-2, FOR-604-IS 63/1-1, IS 63/1-2, FOR-604-EL 270/3-1, EL 270/3-2, FOR-604-CA 618/1-1, CA 618/1-2]
- Forschergruppe of the Deutsche Forschungsgemeinschaft Signalling Pathways in the Healthy and Diseased Heart [FOR 604]
- Herzfeldersche Familienstiftung
- Wellcome Trust [084068, 082837]
- FFM program of University Medical Centre Hamburg-Eppendorf
- Austrian Science Fund (FWF) [P 22385] Funding Source: researchfish
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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.
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