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(Circulation. 2007;115:483-492.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

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

Delvac Oceandy, MD, PhD; Elizabeth J. Cartwright, PhD; Michael Emerson, PhD; Sukhpal Prehar, MSc; Florence M. Baudoin, MRes; Min Zi, MD; Nasser Alatwi, MSc; Luigi Venetucci, PhD; Kai Schuh, PhD; Judith C. Williams, PhD; Angel L. Armesilla, PhD; Ludwig Neyses, MD

From the Division of Cardiovascular and Endocrine Sciences, University of Manchester, Manchester, United Kingdom (D.O., E.J.C., M.E., S.P., F.M.B., M.Z., N.A., L.V., J.C.W., A.L.A., L.N.), and Institut fur Klinische Biochemie und Pathobiochemie, Wurzburg, Germany (K.S.).

Correspondence to Professor Ludwig Neyses, 1.302 Stopford Bldg, University of Manchester, Oxford Rd, Manchester M13 9PT, United Kingdom. E-mail Ludwig.Neyses{at}cmmc.nhs.uk

Received June 5, 2006; accepted November 10, 2006.

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 ß-adrenergic contractile response. This attenuated response was not observed in ct120 transgenic mice. Treatment with a specific nNOS inhibitor (N-propyl-L-arginine) reduced the ß-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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