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J. Biol. Chem., Vol. 279, Issue 19, 19846-19853, May 7, 2004

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Nitric Oxide Inhibition of Adenylyl Cyclase Type 6 Activity Is Dependent upon Lipid Rafts and Caveolin Signaling Complexes^*

Rennolds S. Ostrom, Richard A. Bundey, and Paul A. Insel¶||

From the Department of Pharmacology and the Vascular Biology Center of Excellence University of Tennessee Health Science Center, Memphis, Tennessee 38163 and the Departments of Pharmacology and ^¶Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093

Several cell types, including cardiac myocytes and vascular endothelial cells, produce nitric oxide (NO) via both constitutive and inducible isoforms of NO synthase. NO attenuates cardiac contractility and contributes to contractile dysfunction in heart failure, although the precise molecular mechanisms for these effects are poorly defined. Adenylyl cyclase (AC) isoforms type 5 and 6, which are preferentially expressed in cardiac myocytes, may be inhibited via a direct nitrosylation by NO. Because endothelial NO synthase (eNOS and NOS3), -adrenergic (AR) receptors, and AC6 all can localize in lipid raft/caveolin-rich microdomains, we sought to understand the role of lipid rafts in organizing components of AR-G_s-AC signal transduction together with eNOS. Using neonatal rat cardiac myocytes, we found that disruption of lipid rafts with -cyclodextrin inhibited forskolin-stimulated AC activity and cAMP production, eliminated caveolin-3-eNOS interaction, and increased NO production. AR- and G_s-mediated activation of AC activity were inhibited by -cyclodextrin treatment, but prostanoid receptor-stimulated AC activity, which appears to occur outside caveolin-rich microdomains, was unaffected unless eNOS was overexpressed and lipid rafts were disrupted. An NO donor, SNAP, inhibited basal and forskolin-stimulated cAMP production in both native cardiac myocytes and cardiac myocytes and pulmonary artery endothelial cells engineered to overexpress AC6. These effects of SNAP were independent of guanylyl cyclase activity and were mimicked by overexpression of eNOS. The juxtaposition of eNOS with AR and AC types 5 and 6 results in selective regulation of AR by eNOS activity in lipid raft domains over other G_s-coupled receptors localized in nonraft domains. Thus co-localization of multiple signaling components in lipid rafts provides key spatial regulation of AC activity.

Received for publication, December 9, 2003 , and in revised form, March 1, 2004.

^* This work was supported by National Institutes of Health Grants HL63885, HL53773, and HL71781. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Pharmacology, 0636, University of California, San Diego, La Jolla, CA 92093-0636. Tel.: 858-534-2298; Fax: 858-822-1007; E-mail: pinsel{at}ucsd.edu.

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