Regulation of serotonin-2C receptor G-protein coupling by RNA editing

• Published in: Nature (London) 1997-05, Vol.387 (6630), p.303-308
• Main Authors: Burns, Colleen M, Chu, Hsin, Rueter, Susan M, Hutchinson, Linda K, Canton, Hervé, Sanders-Bush, Elaine, Emeson, Ronald B
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Adenosine - genetics; Adenosine - metabolism; Adenosine Deaminase - genetics; Adenosine Deaminase - metabolism; Animals; Binding, Competitive; Biological and medical sciences; Brain - enzymology; Brain - metabolism; Cell Line; Cell receptors; Cell structures and functions; Choroid Plexus - metabolism; Corpus Striatum - metabolism; Fundamental and applied biological sciences. Psychology; Genetics; GTP-Binding Proteins - metabolism; Hippocampus - metabolism; Humanities and Social Sciences; Humans; Inosine - genetics; Inosine - metabolism; letter; Mice; Molecular and cellular biology; Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine); multidisciplinary; Rats; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin - genetics; Receptors, Serotonin - metabolism; Ribonucleic acid; RNA; RNA Editing; RNA, Messenger - metabolism; RNA-Binding Proteins; Science; Science (multidisciplinary); Serotonin - metabolism; Signal Transduction; Transfection; Tumor Cells, Cultured
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/387303a0

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) elicits a wide array of physiological effects by binding to several receptor subtypes. The 5-HT 2 family of receptors belongs to a large group of seven-transmembrane-spanning G-protein-coupled receptors and includes three receptor subtypes (5-HT 2A , 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 diacylglycerol1. 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 iso-forms 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.