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J. Biol. Chem., Vol. 282, Issue 11, 8332-8342, March 16, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/11/8332    most recent M606946200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Roumy, M. Articles by Mollereau, C. Search for Related Content PubMed PubMed Citation Articles by Roumy, M. Articles by Mollereau, C. Social Bookmarking                      What's this?

Physical Association between Neuropeptide FF and µ-Opioid Receptors as a Possible Molecular Basis for Anti-opioid Activity^*

Michel Roumy, Corinne Lorenzo, Serge Mazères, Stéphanie Bouchet, Jean-Marie Zajac, and Catherine Mollereau¹

From the Institut de Pharmacologie et Biologie Structurale, CNRS UMR 5089, 205 route de Narbonne, 31077 Toulouse cedex 04 and the Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, CNRS UMR 5088, 118 route de Narbonne, 31062 Toulouse cedex 09, France

Neuropeptide FF (NPFF) modulates the opioid system by exerting functional anti-opioid activity on neurons, the mechanism of which is unknown. By using a model of SH-SY5Y cells, we recently postulated that anti-opioid activity likely takes place upstream from the signaling cascade, suggesting that NPFF receptors could block opioid receptors by physical interaction. In the present study, fluorescence techniques were used to monitor the physical association and the dynamic of NPFF₂ and µ-opioid (MOP) receptors tagged with variants of the green fluorescent protein. Importantly, cyan fluorescent protein-tagged NPFF₂ receptors retained their capacity to antagonize opioid receptors. Fluorescence resonance energy transfer (FRET) and coimmunoprecipitation studies indicate that NPFF and MOP receptors are close enough to generate a basal FRET signal. The opioid agonist Tyr-D-Ala-Gly-NMe-Phe-Gly-ol disrupts by 20-30% this FRET signal, mainly because it concomitantly induces 40% internalization of receptors. In contrast, the NPFF analog 1DMe significantly increases by 10-15% the basal FRET signal, suggesting an association between both receptors. In addition, 1DMe reduces, by half, MOP receptor internalization, indicating that, besides a functional blockade of opioid receptors, the NPFF analog also inhibits their internalization. Finally, as a first report showing the modulation of the mobility of a G-protein-coupled receptor by another one, fluorescence recovery after photobleaching analysis reveals that 1DMe [PDB] modifies the lateral diffusion of MOP receptors in the cell membrane, changing them from a confined to a freely diffusing state. By promoting NPFF-MOP receptor heteromerization, 1DMe could disrupt the domain organization of MOP receptors in the membrane, resulting in a reduction of opioid response.

Received for publication, July 21, 2006 , and in revised form, December 7, 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: Tel.: 33-56-117-5922; Fax: 33-56-117-5994; E-mail: catherine.mollereau-manaute{at}ipbs.fr.

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