The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) elicits a wide array of physiological effects by binding to several receptor subtypes. 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-HT(2B) and 5-HT(2C)) which are linked to phospholipase C, promoting the hydrolysis of membrane phospholipids and a subsequent increase in the intracellular levels of inositol phosphates and diacylglycerol. Here we show that transcripts encoding the 2C subtype of serotonin receptor (5-HT(2C)R) 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 have indicated the tissue-specific expression of seven major 5-HT(2C) receptor isoforms encoded by eleven distinct RNA species. Editing of 5-HT(2C)R messenger RNAs alters the amino-acid coding potential of the predicted second intracellular loop of the receptor and can lead to a 10-15-fold reduction in the efficacy of the interaction between receptors and their G proteins. These observations indicate that RNA editing is a new mechanism for regulating serotonergic signal transduction and suggest that this post-transcriptional modification may be critical for modulating the different cellular functions that are mediated by other members of the G-protein-coupled receptor superfamily.

For more than 40 years the hallucinogen lysergic acid diethylamide (LSD) has been known to modify serotonin neurotransmission. With the advent of molecular and cellular techniques, we are beginning to understand the complexity of LSD's actions at the serotonin 5-HTThe serotonin receptor superfamily is composed of 14 members to date which have recently been re-classified based on gene structure, amino acid sequence homology, and intracellular signaling cascades (Hoyer et al. 1994). All but one (5-HT 3 ) of the serotonin receptors couples to G proteins, producing second messengers that regulate cellular functions via phosphorylation/ dephosphorylation of intracellular proteins. The five families of G-protein-coupled receptors (5-HT 1 , 5-HT 2 , 5-HT 4 , 5-HT 5 , and 5-HT 7 ) regulate the two major intracellular second messenger pathways, adenylate cyclase and phospholipase C (for review see Sanders-Bush and Canton 1995). The 5-HT 2 receptor family is composed of three subtypes (5-HT 2A , 5-HT 2B , and 5-HT 2C ) linked via the Gq/11 family of G proteins to activation of phospholipase C with the generation of two second messengers, IP 3 which releases intracellular stores of calcium, and diacylglycerol, which activates protein kinase C. Recently, it has become clear that the 5-HT 2 receptor family also has the ability to activate other intracellular signaling pathways. For example, the 5-HT 2C receptor has been shown to activate phospholipase A 2 (Berg et al. 1996), regulate adenylate cyclase (Lucaites et al. 1996) and increase cyclic GMP (Kaufman et al. 1995). Whether these various signaling pathways are parallel or converging is not yet known, nor is it known what are the relative contribution of these pathways to in vivo function of 5-HT 2C receptors in choroid plexus epithelia and neurons.The ergoline hallucinogenic drug lysergic acid diethylamide (LSD) binds with high affinity to serotonin receptors. Indeed, the early finding that LSD blocks the action of serotonin in smooth muscle (Gaddum 1953;Wooley and Shaw 1954) more than 40 years, we still cannot explain why LSD has such potent and profound effects on perception, mood, and thought processes. Of the many subtypes of serotonin receptors, the action of LSD at the 5-HT 2 family of G-protein-coupled receptors has been most convincingly implicated in the behavioral effects of LSD and other hallucinogenic agents (Titeler et al. 1988). LSD behaves as a partial agonist at 5-HT 2A (Burris et al. 1991;Marek and Aghajanian 1996) and 5-HT 2C receptors (Sanders-Bush et al. 1988;Egan et al. 1998). Because of its partial agonist proterties, LSD has the potential to partially block the effect of serotonin. It is possible that this 5-HT 2A/2C receptor partial agonist property explains the unique behavioral properties of LSD; however, other partial agonists at 5-HT 2A/2C receptors, such as m-CPP and lisuride, do not produce LSD-like behavior in humans (Grotewiel et al. 1994;Titeler et al. 1988). Therefore, there must be something unique about LSD versus serotonin that is re...

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