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RNA Editing of the Human Serotonin 5-HT_2C Receptor Disrupts Transactivation of the Small G-Protein RhoA

Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee

The human serotonin 5-HT_2C receptor undergoes adenosineto-inosine RNA editing at five positions, generating multiple receptor isoforms with altered G-protein coupling properties. In the current study, we demonstrate that RNA editing regulates the pattern of intracellular signaling. The non-edited human 5-HT_2C receptor isoform INI activates phospholipase D via the G₁₃ heterotrimer G-protein. We present evidence that transactivation of the small G-protein RhoA is required for phospholipase D activation. In contrast, neither transactivation of RhoA nor phospholipase D activation was detected in cells expressing the fully edited VGV isoform. The ability to activate phospholipase C is also reduced in VGV-expressing cells, but not to the extent found for the phospholipase D signal. We conclude that RNA editing represents a novel mechanism for regulating 5-HT_2C receptor signaling to pathways linked to actin cytoskeletal organization and regulated exocytosis.

Address correspondence to: Dr. Elaine Sanders-Bush, Vanderbilt University School of Medicine, Vanderbilt Brain Institute, 465 21st Avenue South, 8140 Medical Research Building III, Nashville, TN 37232-8548. E-mail: elaine.bush{at}vanderbilt.edu

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