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Vol. 17, Issue 11, 4619-4631, November 2006

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Opposite Effects of PSD-95 and MPP3 PDZ Proteins on Serotonin 5-Hydroxytryptamine_2C Receptor Desensitization and Membrane Stability

Sophie Gavarini^*, Carine Bécamel^*, Christophe Altier, Philippe Lory^*, Joël Poncet^*, Jan Wijnholds, Joël Bockaert^*, and Philippe Marin^*

*Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203, Institut National de la Santé et de la Recherche Médicale, U661, Université Montpellier I, Université Montpellier II, and Département de Neurobiologie, Institut de Génomique Fonctionnelle, F-34094 Montpellier Cedex 5, France; Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 1N4; and Department of Neuromedical Genetics, The Netherlands Institute for Neurosciences, Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands

Submitted March 21, 2006; Revised July 24, 2006; Accepted August 8, 2006
Monitoring Editor: J. Silvio Gutkind

PSD-95/Disc large/Zonula occludens 1 (PDZ) domain-containing proteins (PDZ proteins) play an important role in the targeting and the trafficking of transmembrane proteins. Our previous studies identified a set of PDZ proteins that interact with the C terminus of the serotonin 5-hydroxytryptamine (5-HT)_2C receptor. Here, we show that the prototypic scaffolding protein postsynaptic density-95 (PSD-95) and another membrane-associated guanylate kinase, MAGUK p55 subfamily member 3 (MPP3), oppositely regulate desensitization of the receptor response in both heterologous cells and mice cortical neurons in primary culture. PSD-95 increased desensitization of the 5-HT_2C receptor-mediated Ca²⁺ response, whereas MPP3 prevented desensitization of the Ca²⁺ response. The effects of the PDZ proteins on the desensitization of the Ca²⁺ response were correlated with a differential regulation of cell surface expression of the receptor. Additional experiments were performed to assess how PDZ proteins globally modulate desensitization of the 5-HT_2C receptor response in neurons, by using a peptidyl mimetic of the 5-HT_2C receptor C terminus fused to the human immunodeficiency virus type-1 Tat protein transduction domain, which disrupts interaction between the 5-HT_2C receptor and PDZ proteins. Transduction of this peptide inhibitor into cultured cortical neurons increased the desensitization of the 5-HT_2C receptor-mediated Ca²⁺ response. This indicates that, overall, interaction of 5-HT_2C receptors with PDZ proteins inhibits receptor desensitization in cortical neurons.

Address correspondence to: Philippe Marin (philippe.marin{at}igf.cnrs.fr)

Abbreviations used: GPCR, G protein-coupled receptor; MAGUK, membrane-associated guanylate kinase; MPP3, MAGUK p55 subfamily member 3; PDZ, PSD-95/Disc large/Zonula occludens 1; PSD-95, postsynaptic density-95; Veli3, vertebrate homologue of Lin7 3.

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