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

Article

关键词: MEMBRANE CA2+ PUMP;    PLASMA-MEMBRANE;    MYOCARDIAL-INFARCTION;    VENTRICULAR MYOCYTES;    PROTEIN;    OVEREXPRESSION;    CA2+-ATPASE;    ALPHA-1-SYNTROPHIN;    CONTRACTILITY;    EXPRESSION;   

DOI  :  10.1161/CIRCULATIONAHA.106.643791

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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