Article (Scientific journals)
Neuronal nitric oxide synthase signaling in the heart is regulated by the sarcolemmal calcium pump 4b.
Oceandy, Delvac; Cartwright, Elizabeth J.; Emerson, Michael et al.
2007In Circulation, 115 (4), p. 483-92
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Keywords :
Adrenergic beta-Agonists/pharmacology; Animals; Calcium/metabolism; Calcium Channels, L-Type/metabolism; Female; Gene Expression; Heart/physiology; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Contraction/physiology; Myocardium/enzymology; Nitric Oxide Synthase Type I/metabolism; Plasma Membrane Calcium-Transporting ATPases/genetics/metabolism; Receptors, Adrenergic, beta/metabolism; Sarcolemma/enzymology; Signal Transduction/physiology
Abstract :
[en] 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 (N omega-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.
Disciplines :
Cardiovascular & respiratory systems
Author, co-author :
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 L.
Neyses, Ludwig ;  University of Luxembourg > Research Office
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Title :
Neuronal nitric oxide synthase signaling in the heart is regulated by the sarcolemmal calcium pump 4b.
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Lippincott Williams & Wilkins, United States - Maryland
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Peer Reviewed verified by ORBi
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