RNA editing is a post-transcriptional modification resulting in an alteration of the primary nucleotide sequence of RNA transcripts by mechanisms other than splicing. The enzymatic conversion of adenosine to inosine by RNA editing has been identified within an increasing number of RNA transcripts, indicating that this modification represents an important mechanism for the generation of molecular diversity. Several of these editing events have been shown to have significant consequences for cellular function. Transcripts encoding the Bsubunit (GluR-B) of the ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype of glutamate receptor undergo RNA editing events that modulate both the ion permeation and electrophysiological characteristics of this glutamate-gated ion channel (1-3). Mice that are deficient in their ability to edit GluR-B transcripts die at 3 weeks of age due to epileptic seizures, suggesting that editing of GluR-B RNA is important in the modulation of normal glutamatergic neurotransmission (4). These results suggest that the consequences of editing events within other, diverse RNA molecules might also have important ramifications for cellular function.The monoamine 5-hydroxytryptamine (serotonin; 5-HT) 1 interacts with a large family of receptors to induce signal transduction events important in the modulation of neurotransmission (5). The 2C subtype of serotonin receptor (5-HT 2C R) is a member of the G protein-coupled receptor superfamily and stimulates phospholipase C, resulting in the production of inositol phosphates and diacylglycerol (6). We have recently shown that RNA transcripts encoding the rat, mouse, and human 5-HT 2C R undergo adenosine-to-inosine RNA editing events at five positions, termed A, B, C, D, and E (previously termed CЈ) (7,8), resulting in an alteration of amino acid coding potential within the putative second intracellular loop of the encoded protein. Editing at the A site, or at the A and B sites concurrently, converts an isoleucine to a valine at amino acid 156 of the human receptor, while editing at the B position alone generates a methionine codon at this site (Fig. 1A). Editing at C converts asparagine 158 to a serine; editing at E generates an aspartate at this site, and conversion at both C and E generates a glycine triplet. Editing at D results in the substitution of a valine for an isoleucine at position 160.We have previously demonstrated a decrease in 5-HT potency when interacting with the rat 5-HT 2C R isoform 5-HT 2C-VSV , which is simultaneously edited at the A, B, C, and D positions encoding valine, serine, and valine at positions 157, 159, 161, respectively. This decrease in potency was reflected as a rightward shift in the dose-response curve for [ 3 H]inositol monophosphate accumulation (7). We proposed that the decreased potency resulted from a reduced G protein coupling efficiency induced by the introduction of novel amino acids into the second intracellular loop, a region known to be important for G protein coupling (9 -16). In the present study,...