title: Intracellular NAADP increase induced by extracellular NAADP via the P2Y11-like receptor.
abstract: The aim of the study was to identify a signalling pathway allowing NAADP-induced intracellular NAADP increase and involving the P2Y11-like receptor. P2Y11-like and β-adrenergic receptors may play important regulatory roles within the cardiovascular system. Both receptors have been shown to be involved in triggering myocardial preconditioning. Using a Langendorff model we report a positive inotropic response induced by extracellular NAADP via P2Y11-like receptor stimulation. In cardiomyocyte cultures, P2Y11-like receptor stimulation by extracellular NAADP ([NAADP]e) increased intracellular cADP-ribose and NAADP concentration as evidenced by direct measurements. NF546, a new selective P2Y11 receptor agonist, increased intracellular cAMP, cADP-ribose and NAADP concentration confirming the involvement of the P2Y11-like receptor in this signalling pathway. NF157, a P2Y11 receptor antagonist, suppressed the increase in intracellular cADPr, NAADP and NAAD induced by either [NAADP]e or NF546. The response profile for intracellular cADP-ribose and NAADP concentration following P2Y11-like stimulation with NF546 was similar to reported data relating β-adrenergic stimulation with isoprenaline. This response represents the signature of the Gs/ADP-ribosyl cyclase activity. Moreover, this study provides a signalling pathway: intracellular NAADP increase induced by extracellular NAADP via metabotropic activity of P2Y11-like receptor. This pathway implying P2Y11-like could take part in the intracellular calcium rise reported for extracellular NAADP.
authors.affiliation: Department of Pharmacology, E.A.3801, SFR CAP-santé, Reims University Hospital, 51, rue Cognacq-Jay, 51095 Reims Cedex, France. zoubir.djerada@univ-reims.fr
authors.forename: Zoubir
authors.initials: Z
authors.lastname: Djerada
authors.forename: Hervé
authors.initials: H
authors.lastname: Millart
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D036563:Cyclic ADP-Ribose / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D009282:Naphthalenesulfonates / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D058470:Receptors, Purinergic P2Y / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013498:Suramin / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
chemical_list: C546599:4,4'-(carbonylbis(imino-3,1-phenylenecarbonylimino-3,1-(4-methylphenylene)carbonylimino))bis(1,3-xylene-alpha,alpha'-diphosphonic acid); D004164:Diphosphonates; C526891:NF157 compound; D009282:Naphthalenesulfonates; D011943:Receptors, Adrenergic, beta; D058470:Receptors, Purinergic P2Y; D036563:Cyclic ADP-Ribose; D009249:NADP; C024376:NAADP; D013498:Suramin; D000242:Cyclic AMP; D036541:ADP-ribosyl Cyclase