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J. Biol. Chem., Vol. 279, Issue 19, 20257-20266, May 7, 2004

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The Serotonin 5-HT_2A and 5-HT_2C Receptors Interact with Specific Sets of PDZ Proteins^*

Carine Bécamel, Sophie Gavarini, Benjamin Chanrion, Gérard Alonso¶, Nathalie Galéotti, Aline Dumuis, Joël Bockaert, and Philippe Marin||

From the UPR CNRS 2580 and ^¶CNRS UMR 5101, 141 rue de la Cardonille, 34094 Montpellier Cedex 5, France

The 5-hydroxytryptamine type 2A (5-HT_2A) receptor and the 5-HT_2C receptor are closely related members of the G-protein-coupled receptors activated by serotonin that share very similar pharmacological profiles and cellular signaling pathways. These receptors express a canonical class I PDZ ligand (SXV) at their C-terminal extremity. Here, we have identified proteins that interact with the PDZ ligand of the 5-HT_2A and 5-HT_2C receptors by a proteomic approach associating affinity chromatography using immobilized synthetic peptides encompassing the PDZ ligand and mass spectrometry. We report that both receptor C termini interact with specific sets of PDZ proteins in vitro. The 5-HT_2C receptor but not the 5-HT_2A receptor binds to the Veli-3·CASK·Mint1 ternary complex and to SAP102. In addition, the 5-HT_2C receptor binds more strongly to PSD-95 and MPP-3 than the 5-HT_2A receptor. In contrast, a robust interaction between the 5-HT_2A receptor and the channel-interacting PDZ protein CIPP was found, whereas CIPP did not significantly associate with the 5-HT_2C receptor. We also show that residues located at the -1 position and upstream the PDZ ligand in the C terminus of the 5-HT_2A and 5-HT_2C receptors are major determinants in their interaction with specific PDZ proteins. Immunofluorescence and electron microscopy studies strongly suggested that these specific interactions also take place in living cells and that the 5-HT₂ receptor-PDZ protein complexes occur in intracellular compartments. The interaction of the 5-HT_2A and the 5-HT_2C receptor with specific sets of PDZ proteins may contribute to their different signal transduction properties.

Received for publication, November 5, 2003 , and in revised form, February 24, 2004.

^* This work was supported by grants from the CNRS, Hoechst-Marion Roussel, French Ministère de la Recherche et de la Technologie Grant ACI JC 5075, and by Montpellier Languedoc-Roussillon Genopole. 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.

Contributed equally to this article.

Recipient of a fellowship of the Fondation pour la Recherche Médicale.

^|| To whom correspondence should be addressed. Tel.: 33-4-67-14-29-83; Fax: 33-4-67-14-29-10; E-mail: philippe.marin{at}ccipe.cnrs.fr.

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