RNA Editing of the Human Serotonin 5-Hydroxytryptamine 2C Receptor Silences Constitutive Activity*
C. Niswender, Sara C. Copeland, K. Herrick‐Davis, R. Emeson, Elaine Sanders‐bush
Journal of Biological Chemistry April 2, 1999 DOI: 10.1074/jbc.274.14.9472 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Human and rat brain samples; NIH-3T3 fibroblasts expressing receptor variants |
| Intervention | serotonergic agonists |
| Topics | Serotonin |
| Key findings | RNA editing of the 5-HT2C receptor reduces agonist potency and G protein coupling, primarily by silencing the receptor's constitutive activity. |
Abstract
RNA transcripts encoding the serotonin 5-hydroxytryptamine 2C (5-HT2C) receptor (5-HT2CR) undergo adenosine-to-inosine RNA editing events at up to five specific sites. Compared with rat brain, human brain samples expressed higher levels of RNA transcripts encoding the amino acids valine-serine-valine (5-HT2C-VSV) and valine-glycine-valine (5-HT2C-VGV) at positions 156, 158, and 160, respectively. Agonist stimulation of the nonedited human receptor (5-HT2C-INI) and the edited 5-HT2C-VSVand 5-HT2C-VGV receptor variants stably expressed in NIH-3T3 fibroblasts demonstrated that serotonergic agonists were less potent at the edited receptors. Competition binding experiments revealed a guanine nucleotide-sensitive serotonin high affinity state only for the 5-HT2C-INI receptor; the loss of high affinity agonist binding to the edited receptor demonstrates that RNA editing generates unique 5-HT2CRs that couple less efficiently to G proteins. This reduced G protein coupling for the edited isoforms is primarily due to silencing of the constitutive activity of the nonedited 5-HT2CR. The distinctions in agonist potency and constitutive activity suggest that different edited 5-HT2CRs exhibit distinct responses to serotonergic ligands and further imply that RNA editing represents a novel mechanism for controlling physiological signaling at serotonergic synapses.
Comparable studies
Other experimental studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers | 1998 | Experimental study | |
| Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | 2000 | Experimental study | |
| Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain | 1988 | Experimental study | |
| The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... | 1992 | Laboratory study | |
| 5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Rat brain | 1997 | Experimental study |
Citations in the library
Cited by 7
- PSD-95 Is Essential for Hallucinogen and Atypical Antipsychotic Drug Actions at Serotonin Receptors Journal of Neuroscience June 3, 2009
- Agonist-Directed Signaling of Serotonin 5-HT2C Receptors Differences Between Serotonin and Lysergic Acid Diethylamide (LSD) Neuropsychopharmacology August 1, 1999
- Molecular insights into the regulation of constitutive activity by RNA editing of 5HT2C serotonin receptors Cell Reports August 1, 2022
- Making Sense of Psychedelics in the CNS The International Journal of Neuropsychopharmacology January 30, 2024
- Serotonin 5-HT2C Receptor Signaling Analysis Reveals Psychedelic Biased Agonism. ACS Chemical Neuroscience September 13, 2025
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