RNA editing of the 5-HT2C receptor is reduced in schizophrenia

Sodhi, Monsheel S.; Burnet, Philip W.J.; Makoff, Andrew; Kerwin, Robert; Harrison, Paul J.

doi:10.1038/sj.mp.4000920

Cited by 154 publications

(129 citation statements)

References 24 publications

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“…Changes in this receptor signaling may be related to the PPI deficit identified in the ADAR2 KO mice. Interestingly, these findings are in accordance with an analogous PPI deficit in schizophrenic patients (32), showing altered editing of the 5-HT2C receptor pre-mRNA in the prefrontal cortex (33). An altered 5-HT2C receptor function might contribute to the hearing deficit in the ADAR2 KO mice, as this receptor is expressed in both the cochlea (34) and inferior colliculus (35).…”

Section: Discussionsupporting

confidence: 73%

Requirement of the RNA-editing Enzyme ADAR2 for Normal Physiology in Mice

Horsch

Seeburg

Adler

et al. 2011

Journal of Biological Chemistry

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ADAR2, an RNA editing enzyme that converts specific adenosines to inosines in certain pre-mRNAs, often leading to amino acid substitutions in the encoded proteins, is mainly expressed in brain. Of all ADAR2-mediated edits, a single one in the pre-mRNA of the AMPA receptor subunit GluA2 is essential for survival. Hence, early postnatal death of mice lacking ADAR2 is averted when the critical edit is engineered into both GluA2 encoding Gria2 alleles. Adar2 ؊/؊ /Gria2 R/R mice display normal appearance and life span, but the general phenotypic effects of global lack of ADAR2 have remained unexplored. Here we have employed the Adar2 ؊/؊ /Gria2 R/R mouse line, and Gria2 R/R mice as controls, to study the phenotypic consequences of loss of all ADAR2-mediated edits except the critical one in GluA2. Our extended phenotypic analysis covering ϳ320 parameters identified significant changes related to absence of ADAR2 in behavior, hearing ability, allergy parameters and transcript profiles of brain.The most common RNA modification in higher organisms is the enzymatic deamination of specific adenosines to inosine (A-to-I editing), wrought by members of the ADAR protein family (1). ADARs, short for adenosine deaminases acting on RNA, were discovered by their ability to convert in vitro in double-stranded RNA ϳ50% of the adenosines to inosines, thus destabilizing the double-stranded structure (2). Occurring in worms, flies and mammals, these enigmatic enzymes are now known to switch specific adenosines to inosine in mostly primary nuclear transcripts (3-6). A-to-I editing often recodes amino acids within the gene-encoded protein, based on reading inosine as guanosine by the translational machinery, and can remove or create splice acceptor sites (7), thus altering the pattern of RNA splicing. Moreover, editing in 5Ј and 3ЈUTRs and intronic sequence may lead to altered translational efficiency,

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Section: Discussionsupporting

confidence: 73%

Requirement of the RNA-editing Enzyme ADAR2 for Normal Physiology in Mice

Horsch

Seeburg

Adler

et al. 2011

Journal of Biological Chemistry

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“…The isoform-dependent constitutive activity could have important implications for the physiological effects of 5-HT by controlling basal tone and sensitivity at synaptic sites. In addition, region-specific generation of edited isoforms (3), coupled with reports of altered RNA editing in suicide (36) and schizophrenia patients (37), suggests that the repertoire of expressed edited 5-HT 2C Rs may contribute to individual differences in brain serotonergic signaling and perhaps even responses to therapeutic agents such as atypical antipsychotic drugs, many of which have been shown to be inverse agonists at the 5-HT 2C R (34,38).…”

Section: Discussionmentioning

confidence: 99%

RNA Editing of the Human Serotonin 5-HT2CReceptor Alters Receptor-mediated Activation of G13Protein

Price¹,

Weiner²,

Chang³

et al. 2001

Journal of Biological Chemistry

100

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The recent completion of the human genome predicted the presence of only 30,000 genes, stressing the importance of mechanisms that increase molecular diversity at the post-transcriptional level. One such posttranscriptional event is RNA editing, which generates multiple protein isoforms from a single gene, often with profound functional consequences. The human serotonin 5-HT 2C receptor undergoes RNA editing that creates multiple receptor isoforms. One consequence of RNA editing of cell surface receptors may be to alter the pattern of activation of heterotrimeric G-proteins and thereby shift preferred intracellular signaling pathways. We examined the ability of the nonedited 5-HT 2C receptor isoform (INI) and two extensively edited isoforms, VSV and VGV, to interact with various G-protein ␣ subunits. Two functional assays were utilized: the cellbased functional assay, Receptor Selection/Amplification Technology TM , in which the pharmacological consequences of co-expression of 5HT 2C receptor isoforms with G-protein ␣ subunits in fibroblasts were studied, and 5HT 2C receptor-mediated rearrangements of the actin cytoskeleton in stable cell lines. These studies revealed that the nonedited 5-HT 2C receptor functionally couples to G q and G 13 . In contrast, coupling to G 13 was not detected for the extensively edited 5-HT 2C receptors. Thus, RNA editing represents a novel mechanism for regulating the pattern of activation of heterotrimeric G-proteins, molecular switches that control an enormous variety of biological processes.The monoamine 5-hydroxytryptamine (serotonin; 5-HT) 1 interacts with a large family of receptors to induce signal transduction events important in the modulation of neurotransmission (1). The 2C subtype of serotonin receptor (5-HT 2C R) is a member of the G-protein-coupled receptor superfamily and interacts with G q to stimulate phospholipase C, resulting in the production of inositol phosphates and diacylglycerol (2). RNA transcripts encoding the human 5-HT 2C R undergo adenosineto-inosine RNA editing events at five positions, termed A, B, C, D, and E (Fig. 1A), altering the amino acid coding potential within the putative second intracellular loop of the protein (3, 4). We and others have demonstrated a decrease in agonist potency at the human edited VSV and VGV isoforms (named for the amino acids at positions 156, 158, and 160) compared with the nonedited isoform, which codes for INI at these positions. This decrease in agonist potency is reflected as a rightward shift in the dose-response curve for inositol phosphate accumulation (5, 6) and calcium release (7). The decreased agonist potency was proposed to result from a reduced G qprotein coupling efficiency induced by the introduction of these novel amino acids into the second intracellular loop, a region known to be important for G-protein coupling (8 -16). Another consequence of RNA editing may be to alter the specificity of activation of heterotrimeric G-proteins and thereby shift intracellular signaling pathways. To test this hypothesi...

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“…This has led to the idea that trait variation in 5-HT2C-R editing could contribute to differences in stress reactivity in the mouse and, by extension, increase risk for stress-related disorders in the human (Schmauss, 2003). Intriguingly, a number of studies have found increased 5-HT2C-R editing in the mPFC of schizophrenics and depressive suicides (Gurevich et al, 2002;Sodhi et al, 2001). There is also preliminary evidence that structural variants in the human HTR2C gene, including a Cys23Ser SNP, are associated with bipolar disorder and major depression (Lappalainen et al, 1999;Lerer et al, 2001;Massat et al, 2007).…”

Section: -Ht2c Receptorsmentioning

confidence: 99%

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Holmes

2008

Neuroscience & Biobehavioral Reviews

249

166

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The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research.

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RNA editing of the 5-HT2C receptor is reduced in schizophrenia

Abstract: 5-HT

Cited by 154 publications

References 24 publications

Requirement of the RNA-editing Enzyme ADAR2 for Normal Physiology in Mice

Requirement of the RNA-editing Enzyme ADAR2 for Normal Physiology in Mice

RNA Editing of the Human Serotonin 5-HT2CReceptor Alters Receptor-mediated Activation of G13Protein

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

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