Messenger RNA editing of the human serotonin 5-HT2C receptor

RNA encoding the rat serotonin 5-HT2C receptor undergoes editing whereby am to four adenosines nm converted to inosines. This conversion can change up to three codons out of a stretch of five in the second intracellular loop of the receptor. RNA editing of the rat 5-HT2C receptor that changes all th ree codons was shown previously to alter intracellular signaling by 5-HT wi thout changing ifs receptor-binding affinity. We analyzed 5-HT2C receptor e diting in human brain and hypothalamic RNA samples and confirmed that all f our adenosine editing sites observed in rat were also present in human samp les. Additionally, we identified a novel editing site in the middle edited codon that extends the repertoire of 5-HT2C receptors by six additional pro tein isoforms. We observed that editing reduces both the binding affinity a nd functional potency of agonists for recombinant human 5-HT2C receptor iso forms. This effect on binding affinity was proportional to the agonist's in trinsic activity, with full agonists most affected, and antagonists showing no effect. These data suggest that RNA editing may alter coupling energeti cs within the ternary complex, thereby altering agonist binding affinities, G protein coupling, and functional responses. RNA editing may thus provide a novel mechanism for regulating 5-HT synaptic signaling and plasticity. ( C) 1999 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.