RNA editing of the serotonin 5HT2C receptor and its effects on cell signalling, pharmacology and brain function

Werry, Timothy David; Loiacono, Richard; Sexton, Patrick M.; Christopoulos, Arthur

doi:10.1016/j.pharmthera.2008.03.012

Cited by 153 publications

(174 citation statements)

References 118 publications

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“…Therefore, we included both the unedited 5-HT2C receptor and the partly edited 5-HT2C-VSV receptor, which is the most abundantly expressed 5-HT2C receptor isoform in human brain. Indeed, the 5-HT2C-VSV receptor isoform is particularly abundant in the hypothalamus 65,67 , where an increased 5-HT2C receptor editing has been linked with changes in feeding behaviour and fat mass 38,66,68 . Noteworthy increases in FRET levels, as addition, a similar attenuation of the GHS-R1a-mediated intracellular calcium mobilization upon co-expression of the 5-HT2C receptor was observed when the synthetic GHS-R1a ligand, MK0677, was used (Figure 2 B).…”

Section: Resultsmentioning

confidence: 99%

Ghrelin’s Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction

Schellekens¹,

Francesco²,

Kandil³

et al. 2015

ACS Chem. Neurosci.

107

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Understanding the intricate pathways modulating appetite and subsequent food intake is of particular importance considering the rise in obesity incidence across the globe. The serotonergic system, specifically the 5-HT2C receptor, has shown to be of critical importance in the regulation of appetite and satiety. The GHS-R1a receptor is another key receptor wellknown for its role in the homeostatic control of food intake and energy balance. We recently showed compelling evidence for an interaction between the GHS-R1a receptor and the 5-HT2C receptor in an in vitro cell line system heterologously expressing both receptors. Here, we investigated this interaction further. First, we show that the GHS-R1a/5-HT2C dimer-induced attenuation of calcium signalling is not due to coupling to GαS, as no increase in cAMP signalling is observed. Next, flowcytometry fluorescence resonance energy transfer (fcFRET) is used to further demonstrate the direct interaction between the GHS-R1a receptor and 5-HT2C receptor.In addition, we demonstrate co-localized expression of the 5-HT2C and GHS-R1a receptor in cultured primary hypothalamic-and hippocampal rat neurons, supporting the biological relevance of a physiological interaction. Furthermore, we demonstrate that when 5-HT2C receptor signalling is blocked, ghrelin's orexigenic effect is potentiated in vivo. In contrast, the specific 5-HT2C receptor agonist lorcaserin, recently approved for the treatment of obesity, attenuates ghrelin-induced food intake. This underscores the biological significance of our in vitro findings of 5-HT2C receptor-mediated attenuation of GHS-R1a receptor activity. Together, this study demonstrates, for the first time, that the GHS-R1a/5-HT2C receptor interaction translates into biological significant modulation of ghrelin's orexigenic effect. This data highlights the potential development of a combined GHS-R1a and 5-HT2C receptor treatment strategy in weight management. ACS Paragon Plus Environment ACS Chemical Neuroscience 5

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Section: Resultsmentioning

confidence: 99%

Ghrelin’s Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction

Schellekens¹,

Francesco²,

Kandil³

et al. 2015

ACS Chem. Neurosci.

107

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“…The tertiary structure of the 5-HT2C mRNA and the loop sequence regions also vary widely among humans, rats, and mice (33,34), although the editing area exists in a loop in all species. These observations may indicate that 5-HT2C mRNA editing can adapt to environmental changes depending on the energetic instability of the RNA.…”

Section: Rna Editing (Fig 1)mentioning

confidence: 99%

Serotonin 2C Receptor as a Superhero: Diversities and Talents in the RNA Universe for Editing, Variant, Small RNA and Other Expected Functional RNAs

Tohda

2014

J Pharmacol Sci

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The serotonin 2C receptor subtype (5-HT2C) seems to have various physiological roles in addition to the function of the receptor. The serotonin receptors are classified into many subtypes (1), especially more than 10 splicing variants have been reported for the 5-HT4 subtype (1, 2), which has been recently reported to be involved in the circadian clock (3, 4). Among the various serotonin receptor subtypes, 5-HT2C is especially interesting. The history of studies on 5-HT2C can also convey its distinct personality. We are often surprised and puzzled by novel discoveries about 5-HT2C. In this review, the "curriculum vitae" of 5-HT2C is first introduced, followed by a discussion of the unique world of 5-HT2C, including RNA editing, short variants, relationship with small RNA, therapeutic potential for functional mental disease (FMD) such as depression and schizophrenia, and the "friendship" with Wakan-yaku (Sino-Japanese traditional medicine). Curriculum vitae of 5-HT2C5-HT2C was previously named 5-HT 1C . Therefore, searches for papers about the receptor written before 1992 must use "5-HT 1C " as the keyword. The serotonin receptor was previously classified into 5-HT 1 and 5-HT 2 by the receptor's affinity for serotonin; 5-HT 1 has approximately 100 times greater affinity for serotonin than does 5-HT 2 . This is caused by the historical background when the "receptor binding assay" was the mainstream method of receptor studies. Each receptor subtype was further subdivided by drug affinities. Thereafter, when the mainstream experimental techniques shifted to second messenger systems, it was clarified that the 5-HT 1 group is coupled to the cAMP system and that the 5-HT 2 group is linked with the inositolphosphate turnover system. However, one subtype of 5-HT 1 did not fulfill this classification: 5-HT 1C . Therefore, with the approval of all scientists, 5-HT 1C was transferred to the 5-HT 2 family and renamed 5-HT2C (5).When this receptor was still called 5-HT 1C , receptor cloning was performed by the "functional cloning method" using Xenopus oocytes injected with an RNA library followed by electrophysiological detection. 13, 2014; Accepted October 13, 2014 Abstract. The serotonin 2C receptor subtype (5-HT2C) has a unique profession and continues to provide exciting and critical new information. The 5-HT2C is modulated at the RNA level by several mechanisms, including editing, short variant generation, and small RNAs. Recently, these phenomena, which had been demonstrated individually, were shown to be associated with each other. At present, many reports provide information about the influence of RNA regulation on receptor protein activities and expression, which was thought to be the final functional product. However, complicated behavior at the RNA stage allows us to imagine that the RNA itself has functional roles in the RNA universe. The 5-HT2C RNA may play several roles. This review will outline previous 5-HT2C studies and prospects for future studies.

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“…In addition, the 5-HT 2C receptor has a diverse spectrum of pharmacological properties, including constitutive (ligand-independent) activity, pleiotropic intracellular signaling effects, and agonist-directed trafficking of receptors (Werry et al, 2008). Therefore, it is not surprising that different pharmacological agents elicit varying physiological and behavioral effects (Navailles and De Deurwaerdère, 2011), as reported for the two 5-HT 2C receptor antagonists whose effects were investigated in the 5-CSRTT.…”

Section: Introductionmentioning

confidence: 98%

Impact of Serotonin (5-HT)2C Receptors On Executive Control Processes

Pennanen

Hart

et al. 2012

Neuropsychopharmacol

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Although the serotonin (5-hydroxytryptamine, 5-HT) neurotransmitter system has been implicated in modulating executive control processes such as attention, response inhibition, and behavioral flexibility, the contributions of particular serotonin receptors remain unclear. Here, using operant-based behavioral paradigms, we demonstrate that mice with genetically ablated 5-HT 2C receptors (2CKO mice) display deficits in executive functions. 2CKO mice were impaired in the acquisition of a visuospatial attention task as assessed in the 5-choice serial reaction time task (5-CSRTT). In this task, 2CKO mice exhibited marked impairment of attentional processes, with normal response inhibition. We assessed dynamic changes in neurotransmitter levels within the nucleus accumbens (NAc) by in vivo microdialysis in task-performing animals. Extracellular dopamine concentrations were elevated in the NAc of 2CKO mice during task performance, indicating that 5-HT 2C receptors impact dopamine homeostasis during a visuospatial attention task. These findings raise the possibility that disinhibition of mesolimbic dopamine pathways contributes to impaired attention and perturbed task performance in 2CKO mice. Additionally, in a spatial reversal learning task, 2CKO mice failed to improve their performance over a series of reversals, indicating that intact 5-HT 2C receptor signaling is required to accurately respond to repeated changes in reward contingencies. In contrast to the 2CKO phenotype in the 5-CSRTT, wild-type mice treated with the 5-HT 2C receptor antagonist SB242084 exhibited diminished response inhibition, suggesting differing effects of acute pharmacological blockade and constitutive loss of 5-HT 2C receptor activity. Altogether, these findings provide insights into the serotonergic regulation of executive control processes and suggest that impaired 5-HT 2C receptor signaling during development may predispose to executive function disorders.

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RNA editing of the serotonin 5HT2C receptor and its effects on cell signalling, pharmacology and brain function

Cited by 153 publications

References 118 publications

Ghrelin’s Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction

Ghrelin’s Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction

Serotonin 2C Receptor as a Superhero: Diversities and Talents in the RNA Universe for Editing, Variant, Small RNA and Other Expected Functional RNAs

Impact of Serotonin (5-HT)2C Receptors On Executive Control Processes

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