Neuronal Nitric Oxide Synthase Signaling in the Heart Is Regulated by the Sarcolemmal Calcium Pump 4b.

2.50
Hdl Handle:
http://hdl.handle.net/2436/15807
Title:
Neuronal Nitric Oxide Synthase Signaling in the Heart Is Regulated by the Sarcolemmal Calcium Pump 4b.
Authors:
Oceandy, Delvac; Cartwright, Elizabeth J.; Emerson, Michael; Prehar, Sukhpal; Baudoin, Florence M.; Zi, Min; Alatwi, Nasser; Venetucci, Luigi; Schuh, Kai; Williams, Judith C.; Armesilla, Angel Luis; Neyses, Ludwig
Abstract:
BACKGROUND: 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.
Citation:
Circulation, 115: 483-492.
Publisher:
American Heart Association
Issue Date:
2007
URI:
http://hdl.handle.net/2436/15807
DOI:
10.1161/CIRCULATIONAHA.106.643791
PubMed ID:
17242280
Additional Links:
http://circ.ahajournals.org/cgi/content/abstract/115/4/483
Type:
Article
Language:
en
Description:
Metadata only
ISSN:
1524-4539
Appears in Collections:
Molecular Pharmacology Research Group

Full metadata record

DC FieldValue Language
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.en
dc.identifier.issn1524-4539-
dc.identifier.pmid17242280-
dc.identifier.doi10.1161/CIRCULATIONAHA.106.643791-
dc.identifier.urihttp://hdl.handle.net/2436/15807-
dc.descriptionMetadata onlyen
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.en
dc.language.isoenen
dc.publisherAmerican Heart Associationen
dc.relation.urlhttp://circ.ahajournals.org/cgi/content/abstract/115/4/483en
dc.subjectNeuronal nitric oxide synthaseen
dc.subjectnNOSen
dc.subjectSignal Transductionen
dc.subjectCalciumen
dc.subjectCardiac contractilityen
dc.titleNeuronal Nitric Oxide Synthase Signaling in the Heart Is Regulated by the Sarcolemmal Calcium Pump 4b.en
dc.typeArticleen

Related articles on PubMed

All Items in WIRE are protected by copyright, with all rights reserved, unless otherwise indicated.