Regulation of serotonin-2C receptor G-protein coupling by RNA editing.
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.
Burns
C M
CM
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6600, USA.
Chu
H
H
Rueter
S M
SM
Hutchinson
L K
LK
Canton
H
H
Sanders-Bush
E
E
Emeson
R B
RB
D016475:3T3 Cells; D000241:Adenosine / Q000235:genetics / Q000378:metabolism; D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D002460:Cell Line; D002831:Choroid Plexus / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007288:Inosine / Q000235:genetics / Q000378:metabolism; D051379:Mice; D017393:RNA Editing; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D051381:Rats; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000235:genetics* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012701:Serotonin; D007288:Inosine; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; D019204:GTP-Binding Proteins; D000241:Adenosine