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Biochem. J. (2006) 396 (401–409) (Printed in Great Britain)

Review article

Subcellular targeting and trafficking of nitric oxide synthases

Stefanie OESS*, Ann ICKING*, David FULTON†, Roland GOVERS‡ and Werner MÜLLER-ESTERL*1

*Institute of Biochemistry II, University of Frankfurt Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany, †Vascular Biology Center and Pharmacology, Medical College of Georgia, 1459 Laney Walker Boulevard, Augusta, GA 30912-2500, U.S.A., and ‡INSERM U568, Faculté de Médecine, 28, avenue de Valombrose, 06107 Nice, France

Unlike most other endogenous messengers that are deposited in vesicles, processed on demand and/or secreted in a regulated fashion, NO (nitric oxide) is a highly active molecule that readily diffuses through cell membranes and thus cannot be stored inside the producing cell. Rather, its signalling capacity must be controlled at the levels of biosynthesis and local availability. The importance of temporal and spatial control of NO production is highlighted by the finding that differential localization of NO synthases in cardiomyocytes translates into distinct effects of NO in the heart. Thus NO synthases belong to the most tightly controlled enzymes, being regulated at transcriptional and translational levels, through co- and post-translational modifications, by substrate availability and not least via specific sorting to subcellular compartments, where they are in close proximity to their target proteins. Considerable efforts have been made to elucidate the molecular mechanisms that underlie the intracellular targeting and trafficking of NO synthases, to ultimately understand the cellular pathways controlling the formation and function of this powerful signalling molecule. In the present review, we discuss the mechanisms and triggers for subcellular routing and dynamic redistribution of NO synthases and the ensuing consequences for NO production and action.

Key words: acylation cycle, differential activation, intracellular trafficking, nitric oxide synthase, protein–protein interaction, subcellular targeting.

Abbreviations used: [Ca²⁺]_i, intracellular Ca²⁺ concentration; CaM, calmodulin; EBP50, ezrin/radixin/moesin-binding phosphoprotein-50; EC, endothelial cell; Hsp90, heat-shock protein 90; LDL, low-density lipoprotein; NMDA, N-methyl-D-aspartate; NOS, nitric oxide synthase; eNOS, endothelial NOS; iNOS, inducible NOS; nNOS, neuronal NOS; NOSIP, NOS-interacting protein; NOSTRIN, NOS trafficking inducer; PECAM, platelet/endothelial cell-adhesion molecule; PI3K, phosphoinositide 3-kinase; PM, plasma membrane; PSD, post-synaptic density; sGC, soluble NO-sensitive guanylate cyclase; VEGF, vascular endothelial growth factor.

¹To whom correspondence should be addressed (email wme@biochem2.de).

Received 24 February 2006/31 March 2006; accepted 12 April 2006

Published on the Internet 29 May 2006, doi:10.1042/BJ20060321

The Biochemical Society, London ©2006

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