Journal
NATURE
Volume 416, Issue 6878, Pages 337-340Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/416337a
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Subcellular localization of nitric oxide (NO) synthases with effector molecules is an important regulatory mechanism for NO signalling(1). In the heart, NO inhibits L-type Ca2+ channels 2 but stimulates sarcoplasmic reticulum (SR) Ca2+ release(3-5), leading to variable effects on myocardial contractility. Here we show that spatial confinement of specific NO synthase isoforms regulates this process. Endothelial NO synthase (NOS3) localizes to caveolae(6-8), where compartmentalization with beta-adrenergic receptors and L-type Ca2+ channels(9) allows NO to inhibit beta-adrenergic-induced inotropy(8,10). Neuronal NO synthase (NOS1), however, is targeted to cardiac SR11. NO stimulation of SR Ca2+ release via the ryanodine receptor (RyR) in vitro(3,4) suggests that NOS1 has an opposite, facilitative effect on contractility. We demonstrate that NOS1-deficient mice have suppressed inotropic response, whereas NOS3-deficient mice have enhanced contractility, owing to corresponding changes in SR Ca2+ release. Both NOS1(-/-) and NOS3(-/-) mice develop age-related hypertrophy, although only NOS3(-/-) mice are hypertensive. NOS1/3(-/-) double knockout mice have suppressed beta-adrenergic responses and an additive phenotype of marked ventricular remodelling. Thus, NOS1 and NOS3 mediate independent, and in some cases opposite, effects on cardiac structure and function.
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