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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, RESULTS. Meshes: Adrenergic beta-Agonists, Animals, Calcium, Calcium Channels, L-Type, Female, Gene Expression, Heart, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Myocardial Contraction, Myocardium, Nitric Oxide Synthase Type I, Plasma Membrane Calcium-Transporting ATPases, Receptors, Adrenergic, beta, Sarcolemma, Signal Transduction.
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Is neuronal nitric oxide synthase signaling in the heart regulated by the sarcolemmal calcium pump 4b? Context: 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. 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.
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These data demonstrate the physiological relevance of the interaction between PMCA4b and nNOS and suggests its signaling role in the heart. Final Decision: yes