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dc.contributor.authorOceandy, Delvac
dc.contributor.authorCartwright, Elizabeth J.
dc.contributor.authorEmerson, Michael
dc.contributor.authorPrehar, Sukhpal
dc.contributor.authorBaudoin, Florence M.
dc.contributor.authorZi, Min
dc.contributor.authorAlatwi, Nasser
dc.contributor.authorVenetucci, Luigi
dc.contributor.authorSchuh, Kai
dc.contributor.authorWilliams, Judith C.
dc.contributor.authorArmesilla, Angel Luis
dc.contributor.authorNeyses, Ludwig
dc.date.accessioned2008-01-08T11:08:39Z
dc.date.available2008-01-08T11:08:39Z
dc.date.issued2007
dc.identifier.citationCirculation, 115: 483-492.
dc.identifier.issn1524-4539
dc.identifier.pmid17242280
dc.identifier.doi10.1161/CIRCULATIONAHA.106.643791
dc.identifier.urihttp://hdl.handle.net/2436/15807
dc.descriptionMetadata only
dc.description.abstractBACKGROUND: Neuronal nitric oxide synthase (nNOS) has recently been shown to be a major regulator of cardiac contractility. In a cellular system, we have previously shown that nNOS is regulated by the isoform 4b of plasma membrane calcium/calmodulin-dependent ATPase (PMCA4b) through direct interaction mediated by a PDZ domain (PSD 95, Drosophilia Discs large protein and Zona occludens-1) on nNOS and a cognate ligand on PMCA4b. It remains unknown, however, whether this interaction has physiological relevance in the heart in vivo. METHODS AND RESULTS: We generated 2 strains of transgenic mice overexpressing either human PMCA4b or PMCA ct120 in the heart. PMCA ct120 is a highly active mutant form of the pump that does not interact with or modulate nNOS function. Calcium was extruded normally from PMCA4b-overexpressing cardiomyocytes, but in vivo, overexpression of PMCA4b reduced the beta-adrenergic contractile response. This attenuated response was not observed in ct120 transgenic mice. Treatment with a specific nNOS inhibitor (Nomega-propyl-L-arginine) reduced the beta-adrenergic response in wild-type and ct120 transgenic mice to levels comparable to those of PMCA4b transgenic animals. No differences in lusitropic response were observed in either transgenic strain compared with wild-type littermates. CONCLUSIONS: These data demonstrate the physiological relevance of the interaction between PMCA4b and nNOS and suggests its signaling role in the heart.
dc.language.isoen
dc.publisherAmerican Heart Association
dc.relation.urlhttp://circ.ahajournals.org/cgi/content/abstract/115/4/483
dc.subjectNeuronal nitric oxide synthase
dc.subjectnNOS
dc.subjectSignal Transduction
dc.subjectCalcium
dc.subjectCardiac contractility
dc.titleNeuronal Nitric Oxide Synthase Signaling in the Heart Is Regulated by the Sarcolemmal Calcium Pump 4b.
dc.typeJournal article
html.description.abstractBACKGROUND: Neuronal nitric oxide synthase (nNOS) has recently been shown to be a major regulator of cardiac contractility. In a cellular system, we have previously shown that nNOS is regulated by the isoform 4b of plasma membrane calcium/calmodulin-dependent ATPase (PMCA4b) through direct interaction mediated by a PDZ domain (PSD 95, Drosophilia Discs large protein and Zona occludens-1) on nNOS and a cognate ligand on PMCA4b. It remains unknown, however, whether this interaction has physiological relevance in the heart in vivo. METHODS AND RESULTS: We generated 2 strains of transgenic mice overexpressing either human PMCA4b or PMCA ct120 in the heart. PMCA ct120 is a highly active mutant form of the pump that does not interact with or modulate nNOS function. Calcium was extruded normally from PMCA4b-overexpressing cardiomyocytes, but in vivo, overexpression of PMCA4b reduced the beta-adrenergic contractile response. This attenuated response was not observed in ct120 transgenic mice. Treatment with a specific nNOS inhibitor (Nomega-propyl-L-arginine) reduced the beta-adrenergic response in wild-type and ct120 transgenic mice to levels comparable to those of PMCA4b transgenic animals. No differences in lusitropic response were observed in either transgenic strain compared with wild-type littermates. CONCLUSIONS: These data demonstrate the physiological relevance of the interaction between PMCA4b and nNOS and suggests its signaling role in the heart.


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