title: NAD derived second messengers: Role in spontaneous diastolic Ca(2+) transients in murine cardiac myocytes.
abstract: Strong β-adrenergic stimulation induced spontaneous diastolic Ca(2+) transients (SCTs) in electrically paced murine cardiac myocytes [28]. To obtain further insights into the underlying mechanism, we developed a method for a simultaneous analysis, in which the free luminal Ca(2+) concentration in the sarcoplasmic reticulum (SR) ([Ca(2+)]SR) and the free cytosolic Ca(2+) concentration ([Ca(2+)]i) were measured in parallel in the same cell. Each spontaneous diastolic Ca(2+) transient was exactly mirrored by a decrease of [Ca(2+)]SR. Since antagonism of the Ca(2+) mobilizing second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) was shown to block SCTs in single cardiac myocytes [28], we analyzed the effect of the novel ADP-ribosyl cyclase inhibitor SAN4825 on both cytosolic and intra-luminal Ca(2+) transients upon strong β-adrenergic stimulation. A strong antagonist effect of SAN4825 on SCTs at low micromolar concentrations was observed. Our results suggest that the underlying mechanism of spontaneous diastolic Ca(2+) transients observed upon strong β-adrenergic stimulation is sensitization of type 2 ryanodine receptor by the Ca(2+) releasing activity of the products of ADP-ribosyl cyclase activity.
authors.affiliation: The Calcium Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Warszta
authors.affiliation: The Calcium Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Merle
authors.initials: M
authors.lastname: Nebel
authors.affiliation: The Calcium Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Fliegert
authors.affiliation: The Calcium Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Electronic address: guse@uke.de.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Guse
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000037:antagonists & inhibitors; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001671:Biochemistry / Q000379:methods; D002118:Calcium / Q000032:analysis* / Q000378:metabolism*; D020013:Calcium Signaling; D002478:Cells, Cultured; D004558:Electric Stimulation; D005456:Fluorescent Dyes / Q000032:analysis / Q000378:metabolism; D016257:Fura-2 / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D007211:Indoles / Q000032:analysis / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009243:NAD / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015290:Second Messenger Systems
chemical_list: D000318:Adrenergic beta-Agonists; D005456:Fluorescent Dyes; D006576:Heterocyclic Compounds, 4 or More Rings; D007211:Indoles; C575194:SAN4825; D009243:NAD; C058776:2-(2-(5-carboxy)oxazole)-5-hydroxy-6-aminobenzofuran-N,N,O-triacetic acid; D036541:ADP-ribosyl Cyclase; D007545:Isoproterenol; C048960:indo-1; D002118:Calcium; D016257:Fura-2
keywords: ADP-ribosyl cylase; Calcium signaling; Cardiac myocyte; NAADP; Signal transduction; Spontaneous diastolic Ca(2+) transient