Neuronal nitric oxide synthase signaling in the heart is regulated by the sarcolemmal calcium pump 4b.

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 (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.

journal_name

Circulation

journal_title

Circulation

authors

Oceandy D,Cartwright EJ,Emerson M,Prehar S,Baudoin FM,Zi M,Alatwi N,Venetucci L,Schuh K,Williams JC,Armesilla AL,Neyses L

doi

10.1161/CIRCULATIONAHA.106.643791

subject

Has Abstract

pub_date

2007-01-30 00:00:00

pages

483-92

issue

4

eissn

0009-7322

issn

1524-4539

pii

CIRCULATIONAHA.106.643791

journal_volume

115

pub_type

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