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Regional Differences in the Coupling of 5-Hydroxytryptamine-1A Receptors to G Proteins in the Rat Brain

Unité Mixte de Recherche 677, Institut National de la Santé et de la Recherche Médicale (INSERM)/Université Pierre et Marie Curie, Institut Fédératif 70 des Neurosciences, Facultéde Médecine Pierre et Marie Curie, Paris, France (C.M.L.C., N.H., M.H., L.L.); and INSERM U513, Facultéde Médecine, Créteil, France (S.E.M.)

Numerous data showed that 5-hydroxytryptamine-1A (5-HT_1A) receptors couple to G_o/_i proteins for signal transduction. However, the subunit isoforms really involved in 5-HT_1A receptor coupling in brain remain to be identified. Moreover, regional differences in the functional characteristics of brain 5-HT_1A receptors have been evidenced repeatedly. Because such differences could be due to variations in G proteins interacting with the same receptor, relevant approaches were used for identifying subunits physically coupled to 5-HT_1A receptors in different regions of the rat brain. Using immunoaffinity chromatography coupled to Western blot detection, 5-HT_1A receptors were found to interact equally with G_o and G_i3 in the cerebral cortex, mainly with G_o and weakly with G_i3 in the hippocampus and exclusively with G_i3 in the anterior raphe area. In the hypothalamus, 5-HT_1A receptors seemed to be coupled to the latter two G proteins plus G_i1 and G_z. Complementary experiments based on an antibody capture technique coupled to both classic radioactivity and scintillation proximity assay detections showed that hippocampal 5-HT_1A receptor stimulation induced 5'-O-(3-[³⁵S]thio)triphosphate binding to immunoprecipitates with G_i3 and G_o antisera. In the anterior raphe, such 5-HT_1A receptor-mediated effect was obtained with G_i3 antiserum only. These results demonstrated the existence of regional differences in the coupling of 5-HT_1A receptors to G proteins in the rat brain. In the anterior raphe, 5-HT_1A receptors seem to interact specifically with G_i3, whereas in the hippocampus, they are mainly coupled to G_o proteins. Such a disparity in G-protein coupling might explain regional differences in adaptive regulations of brain 5-HT_1A receptors.

Address correspondence to: Dr. L. Lanfumey, UMR 677 INSERM/UPMC, Neuropsychopharmacologie, Facultéde Médecine Pierre et Marie Curie, Site Pitié-Salpétrière, 91, Boulevard de l'Hôpital, 75634 Paris Cedex 13, France. E-mail: lanfumey{at}ext.jussieu.fr

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