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J. Biol. Chem., Vol. 283, Issue 27, 18513-18521, July 4, 2008

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Plasma Membrane Cholesterol Content Affects Nitric Oxide Diffusion Dynamics and Signaling^*

Shane Miersch, Michael Graham Espey, Ruchi Chaube, Arzu Akarca, Rodney Tweten^¶, Sirinart Ananvoranich, and Bulent Mutus¹

From the Department of Chemistry and Biochemistry University of Windsor, Windsor Ontario N9B 3P4, Canada, the ^¶Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, and the Molecular and Clinical Nutrition Section, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-1372

Nitric oxide (NO) signaling is inextricably linked to both its physical and chemical properties. Due to its preferentially hydrophobic solubility, NO molecules tend to partition from the aqueous milieu into biological membranes. We hypothesized that plasma membrane ordering provided by cholesterol further couples the physics of NO diffusion with cellular signaling. Fluorescence lifetime quenching studies with pyrene liposome preparations showed that the presence of cholesterol decreased apparent diffusion coefficients of NO 20–40%, depending on the phospholipid composition. Electrochemical measurements indicated that the diffusion rate of NO across artificial bilayer membranes were inversely related to cholesterol content. Sterol transport-defective Niemann-Pick type C1 (NPC1) fibroblasts exhibited increased plasma membrane cholesterol content but decreased activation of both intracellular soluble guanylyl cyclase and vasodilator-stimulated phosphoprotein (VASP) phosphorylation at Ser²³⁹ induced by exogenous NO exposure relative to their normal human fibroblast (NHF) counterparts. Augmentation of plasma membrane cholesterol in NHF diminished production of both cGMP and VASP phosphorylation elicited by NO to NPC1-comparable levels. Conversely, decreasing membrane cholesterol in NPC1 resulted in the augmentation in both cGMP and VASP phosphorylation to a level similar to those observed in NHF. Increasing plasma membrane cholesterol contents in NHF, platelets, erythrocytes and tumor cells also resulted in an increased level of extracellular diaminofluorescein nitrosation following NO exposure. These findings suggest that the impact of cholesterol on membrane fluidity and microdomain structure contributes to the spatial heterogeneity of NO diffusion and signaling.

Received for publication, January 17, 2008 , and in revised form, April 2, 2008.

^* This work was authored, in whole or in part, by National Institutes of Health staff. This work was supported by a National Suborbital and Educational Research Center (NSERC) Discovery Grant (to M. G. E.) and a Canadian Institutes of Health Research operating (bridging) grant (to B. M.). 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.

¹ To whom correspondence should be addressed: 401 Sunset Ave., Windsor, Ontario N9B 3P4, Canada. Fax: 519-973-7098; E-mail: mutusb{at}uwindsor.ca.

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