title: Nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated calcium signaling and arrhythmias in the heart evoked by β-adrenergic stimulation.
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.
authors.affiliation: Calcium Signalling Group, Department of Biochemistry and Signal Transduction, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Merle
authors.initials: M
authors.lastname: Nebel
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Schwoerer
authors.forename: Dominik
authors.initials: D
authors.lastname: Warszta
authors.forename: Cornelia C
authors.initials: CC
authors.lastname: Siebrands
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Limbrock
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Swarbrick
authors.forename: Ralf
authors.initials: R
authors.lastname: Fliegert
authors.forename: Karin
authors.initials: K
authors.lastname: Weber
authors.forename: Sören
authors.initials: S
authors.lastname: Bruhn
authors.forename: Martin
authors.initials: M
authors.lastname: Hohenegger
authors.forename: Anne
authors.initials: A
authors.lastname: Geisler
authors.forename: Lena
authors.initials: L
authors.lastname: Herich
authors.forename: Susan
authors.initials: S
authors.lastname: Schlegel
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
authors.forename: Heimo
authors.initials: H
authors.lastname: Ehmke
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Guse
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D007545:Isoproterenol / Q000494:pharmacology*; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009249:NADP / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D009539:Nicotinic Acids / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000276:immunology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000473:pathology
chemical_list: C543818:3-carboxy-1-octylcarbamoylmethylpyridinium; D000318:Adrenergic beta-Agonists; D009539:Nicotinic Acids; D019837:Ryanodine Receptor Calcium Release Channel; D009249:NADP; C024376:NAADP; D007545:Isoproterenol
keywords: Calcium; Calcium Intracellular Release; NAADP; Ryanodine Receptor; Signal Transduction
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