REGULATION OF SEROTONIN-2C RECEPTOR G-PROTEIN COUPLING BY RNA EDITING

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) elicits a w ide array of physiological effects by binding to several receptor subt ypes. The 5-HT2 family of receptors belongs to a large group of seven- transmembrane-spanning G-protein-coupled receptors and includes three receptor subtypes (5-HT2A, 5-HT2B and 5-HT2C) which are linked to phos pholipase C, promoting the hydrolysis of membrane phospholipids and a subsequent increase in the intracellular levels of inositol phosphates and diacylglycerol(1). Here we show that transcripts encoding the 2C subtype of serotonin receptor (5-HT2CR) undergo RNA editing events in which genomically encoded adenosine residues are converted to inosines by the action of double-stranded RNA adenosine deaminase(s). Sequence analysis of complementary DNA isolates from dissected brain regions h ave indicated the tissue-specific expression of seven major 5-HT2C rec eptor isoforms encoded by eleven distinct RNA species. Editing of J-HT 2CR messenger RNAs alters the amino-acid coding potential of the predi cted second intracellular loop of the receptor and can lead to a 10-15 -fold reduction in the efficacy of the interaction between receptors a nd their G proteins. These observations indicate that RNA editing is a new mechanism for regulating serotonergic signal transduction and sug gest that this post-transcriptional modification may be critical for m odulating the different cellular functions that are mediated by other members of the G-protein-coupled receptor superfamily.