RNA editing of the human serotonin 5-Hydroxytryptamine 2C receptor silences constitutive activity

RNA transcripts encoding the serotonin 5-hydroxytryptamine 2C (5-HT2C) rece ptor (5-HT2CR) undergo adenosine-to-inosine RNA editing events at up to fiv e specific sites. Compared with rat brain, human brain samples expressed hi gher levels of RNA transcripts encoding the amino acids valine-serine-valin e (5-HT2C-VSV) and valine-glycine-valine (5-HT2C-VGV) at positions 156, 158 , and 160, respectively. Agonist stimulation of the nonedited human recepto r (5-HT2C-INI) and the edited 5-HT2C-VSV and 5-HT2C-VGV receptor variants s tably expressed in NIH-3T3 fibroblasts demonstrated that serotonergic agoni sts were less potent at the edited receptors, Competition binding experimen ts revealed a guanine nucleotide-sensitive serotonin high affinity state on ly for the 5-HT2C-INI receptor; the loss of high affinity agonist binding t o the edited receptor demonstrates that RNA editing generates unique 5-HT(2 C)Rs that couple less efficiently to G proteins. This reduced G protein cou pling for the edited isoforms is primarily due to silencing of the constitu tive activity of the nonedited 5-HT2CR. The distinctions in agonist potency and constitutive activity suggest that different edited 5-HT(2C)Rs exhibit distinct responses to serotonergic ligands and further imply that RNA edit ing represents a novel mechanism for controlling physiological signaling at serotonergic synapses.