Regional differences in the coupling of 5-hydroxytryptamine-1A receptors to G proteins in the rat brain

Numerous data showed that 5-hydroxytryptamine-1A (5-HT1A) receptors couple to G alpha(o)/alpha(i) proteins for signal transduction. However, the alpha subunit isoforms really involved in 5-HT1A receptor coupling in brain remain to be identified. Moreover, regional differences in the functional characteristics of brain 5-HT1A 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 alpha subunits physically coupled to 5-HT1A receptors in different regions of the rat brain. Using immunoaffinity chromatography coupled to Western blot detection, 5-HT1A receptors were found to interact equally with G alpha(o) and G alpha(i3) in the cerebral cortex, mainly with G alpha(o) and weakly with G alpha(i3) in the hippocampus and exclusively with G alpha(i3) in the anterior raphe area. In the hypothalamus, 5-HT1A receptors seemed to be coupled to the latter two G proteins plus G alpha(i1) and G alpha(z). Complementary experiments based on an antibody capture technique coupled to both classic radioactivity and scintillation proximity assay detections showed that hippocampal 5-HT1A receptor stimulation induced 5'-O-(3-[S-35] thio) triphosphate binding to immunoprecipitates with G alpha(i3) and G alpha(o) antisera. In the anterior raphe, such 5-HT1A receptor-mediated effect was obtained with G alpha(i3) antiserum only. These results demonstrated the existence of regional differences in the coupling of 5-HT1A receptors to G proteins in the rat brain. In the anterior raphe, 5-HT1A receptors seem to interact specifically with G alpha(i3), whereas in the hippocampus, they are mainly coupled to G alpha(o) proteins. Such a disparity in G-protein coupling might explain regional differences in adaptive regulations of brain 5-HT1A receptors.