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J. Biol. Chem., Vol. 281, Issue 28, 19156-19171, July 14, 2006

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Regulation of Neuronal Nitric-oxide Synthase Activity by Somatostatin Analogs following SST5 Somatostatin Receptor Activation^*

Pierre Cordelier¹, Jean-Pierre Estève, Souad Najib, Luis Moroder, Nicole Vaysse, Lucien Pradayrol, Christiane Susini, and Louis Buscail

From the INSERM U531, IFR31, Centre Hospitalier Universitaire Rangueil, 31432 Toulouse Cedex 4, France and the Max Planck Institute of Biochemistry, 82152 Martinsried, Germany

Somatostatin receptor SST5 is an inhibitory G protein-coupled receptor that exerts a strong cytostatic effect on various cell types. We reported previously that the SST5 anti-proliferative effect results in the inhibition of mitogen-induced increases in intracellular cGMP levels and MAPK activity. This study was conducted to define the early molecular events accountable for the SST5-mediated anti-proliferative effect. Here, we demonstrate that, in Chinese hamster ovary cells expressing SST5 (CHO/SST5 cells), somatostatin inhibited cell proliferation induced by nitric oxide donors and overexpression of the neuronal nitric-oxide synthase (nNOS) protein isoform. Accordingly, nNOS activity and dimerization were strongly inhibited following SST5 activation by the somatostatin analog RC-160. In CHO/SST5 cells, nNOS was dynamically recruited by the SST5 receptor and phosphorylated at tyrosyl residues following RC-160 treatment. RC-160 induced SST5-p60^src kinase complex formation and subsequent p60^src kinase activation. Coexpression of an inactive p60^src kinase mutant with SST5 blocked RC-160-induced nNOS phosphorylation and inactivation and prevented the SST5-mediated anti-proliferative effect. In CHO/SST5 cells, p60^src kinase associated with nNOS to induce its inactivation by phosphorylation at tyrosyl residues following RC-160 treatment. Using recombinant proteins, we demonstrated that such phosphorylation prevented nNOS homodimerization. Next, surface plasmon resonance and mutation analysis revealed that p60^src directly associated with nNOS phosphorylated Tyr⁶⁰⁴. SST5-mediated inhibition of nNOS activity was demonstrated to be essential to the RC-160 anti-proliferative effect on pancreatic endocrine tumor-derived cells. We therefore identified nNOS as a new p60^src kinase substrate essential for SST5-mediated anti-proliferative action.

Received for publication, March 3, 2006 , and in revised form, April 14, 2006.

^* 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: INSERM U531, IFR31, Inst. Louis Bugnard, CHU Rangueil, Batîment L3, BP 84225, 31432 Toulouse Cedex 4, France. Tel.: 5-6132-2404; Fax: 5-6132-2403; E-mail: pierre.cordelier{at}toulouse.inserm.fr.

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