RNA Editing of the Human Serotonin 5-HT2CReceptor Alters Receptor-mediated Activation of G13Protein

The recent completion of the human genome predicted the presence of only 30,000 genes, stressing the importance of mechanisms that increase molecular diversity at the post-transcriptional level. One such post-transcriptional event is RNA editing, which generates multiple protein isoforms from a single gene, often with profound functional consequences. The human serotonin 5-HT 2C receptor undergoes RNA editing that creates multiple receptor isoforms. One consequence of RNA editing of cell surface receptors may be to alter the pattern of activation of heterotrimeric G-proteins and thereby shift preferred intracellular signaling pathways. We examined the ability of the nonedited 5-HT 2C receptor isoform (INI) and two extensively edited isoforms, VSV and VGV, to interact with various G-protein α subunits. Two functional assays were utilized: the cell-based functional assay, Receptor Selection/Amplification Technology TM , in which the pharmacological consequences of co-expression of 5HT 2C receptor isoforms with G-protein α subunits in fibroblasts were studied, and 5HT 2C receptor-mediated rearrangements of the actin cytoskeleton in stable cell lines. These studies revealed that the nonedited 5-HT 2C receptor functionally couples to G q and G 13 . In contrast, coupling to G 13 was not detected for the extensively edited 5-HT 2C receptors. Thus, RNA editing represents a novel mechanism for regulating the pattern of activation of heterotrimeric G-proteins, molecular switches that control an enormous variety of biological processes.