Regulation of Serotonin 2C Receptor Pre-mRNA Editing by Serotonin

Schmauss, Claudia

doi:10.1016/s0074-7742(05)63004-8

Cited by 29 publications

(23 citation statements)

References 49 publications

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“…47 Because increased 5-HT 2C R editing can hamper the responsivity of this receptor subtype to serotonin, our findings suggest that antidepressant therapies, especially those that involve serotonin reuptake inhibition, may be less effective in blunting suicidal tendencies in a subpopulation of patients with an inherently high level of the VSV isoform. Moreover, the proportion of the VSV isoform could be additionally enhanced in these individuals during the initial stages of SSRI therapy as an adaptation to the augmented levels of serotonin in the synapse 22,42 contributing to suicidality in this vulnerable subgroup of patients.…”

Section: Discussionmentioning

confidence: 99%

Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide

et al. 2007

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Suicide is a major public health problem with B1 million victims each year worldwide. Up to 90% of adults who commit suicide have at least one psychiatric diagnosis such as major depression, bipolar disorder (BPD), schizophrenia (SZ), substance abuse or dependence. A question that has remained unanswered is whether the biological substrates of suicide are distinct from those of the psychiatric disorders in which it occurs. The serotonin 2C receptor (5-HT 2C R) has been implicated in depression and suicide. We, therefore, compared the frequencies of its mRNA editing variants in postmortem prefrontal cortical specimens from subjects who committed suicide or who died from other causes. All suicides occurred in the context of either SZ or BPD. The non-suicide cases included subjects with either SZ or BPD as well as subjects with no psychiatric diagnosis. We identified 5-HT 2C R mRNA editing variations that were associated with suicide but not with the comorbid psychiatric diagnoses, and were not influenced by demographic characteristics (age and sex) and alcohol or drug use. These variations consisted of a significant increase in the pool of mRNA variants (ACD and ABCD) that encode one of the most prevalent and highly edited isoforms of 5-HT 2C R, that is, VSV (Val156-Ser158-Val160). Because the VSV isoform of 5-HT 2C R exhibits low functional activity, an increase in its expression frequency may significantly influence the serotonergic regulation of the brain. Thus, at least in patients with SZ or BPD, overexpression of the VSV isoform in the prefrontal cortex may represent an additional risk factor for suicidal behavior.

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Section: Discussionmentioning

confidence: 99%

Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide

et al. 2007

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“…Human diseases or pathophysiologies can also be caused by dysfunction of the A→I RNA editing mechanism 63,64 . Heterozygosity for the ADAR1-gene functional-null mutation results in dyschromatosis symmetrica hereditaria, a human pigmentary genodermatosis of autosomaldominant inheritance 65 .…”

Section: Rna-editing Deficienciesmentioning

confidence: 99%

“…Q/R-site editing also regulates the tetramerization and intracellular trafficking of the receptor protein 111 . b | Serotonin receptors have important roles in physiological and behavioural processes such as circadian rhythms, emotional control and feeding behaviour 55,64 . G-protein-coupling functions of serotonin (5-HT) receptor-2C (5-HT 2C R) are dramatically reduced by A→I RNA editing that occurs at five sites (A, B, C, D and E sites).…”

Section: Single Nucleotide Polymorphism (Snp)mentioning

confidence: 99%

“…Last, RNA editing of 5-HT 2C R might have some causative relevance to neuropsychiatric disorders, such as depression, as the editing pattern of 5-HT 2C R mRNA (FIG. 3b) is significantly altered in the prefrontal cortex of suicide victims 64,67,68 . …”

mentioning

confidence: 94%

“…3a). Last, the inactivation of ADAR1 leads to an embryonic lethal phenotype that is caused by defective erythropoiesis and widespread apoptosis [60][61][62] .Human diseases or pathophysiologies can also be caused by dysfunction of the A→I RNA editing mechanism 63,64 . Heterozygosity for the ADAR1-gene functional-null mutation results in dyschromatosis symmetrica hereditaria, a human pigmentary genodermatosis of autosomaldominant inheritance 65 .…”

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confidence: 99%

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Editor meets silencer: crosstalk between RNA editing and RNA interference

Nishikura

2006

Nat Rev Mol Cell Biol

257

263

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The most prevalent type of RNA editing is mediated by ADAR (adenosine deaminase acting on RNA) enzymes, which convert adenosines to inosines (a process known as A→I RNA editing) in double-stranded (ds)RNA substrates. A→I RNA editing was long thought to affect only selected transcripts by altering the proteins they encode. However, genome-wide screening has revealed numerous editing sites within inverted Alu repeats in introns and untranslated regions. Also, recent evidence indicates that A→I RNA editing crosstalks with RNA-interference pathways, which, like A→I RNA editing, involve dsRNAs. A→I RNA editing therefore seems to have additional functions, including the regulation of retrotransposons and gene silencing, which adds a new urgency to the challenges of fully understanding ADAR functions.An RNA transcript is subjected to various maturation processes, such as 5′ capping, splicing, 3′ processing and polyadenylation, after it is transcribed from the gene. Post-transcriptional processing of primary transcripts is essential to generate mature messenger RNAs that are ready to be translated into proteins 1 . RNA editing is a post-transcriptional-processing mechanism that results in an RNA sequence that is different from the one encoded by the genome, and thereby contributes to the diversity of gene products. There are different types of RNA-editing mechanism that either add or delete nucleotides, or that change one nucleotide into another 2 (BOX 1).The type of RNA editing that is most prevalent in higher eukaryotes converts adenosine (A) residues into inosine (I) in double-stranded (ds)RNAs through the action of ADAR (adenosine deaminase acting on RNA) enzymes [3][4][5] . A→I RNA editing of a short dsRNA that has formed between a coding exon and nearby intron sequences can lead to a codon change and an alteration in the protein function. However, it was recently discovered that the most frequent targets of A→I RNA editing seem to be long, but partially double-stranded, RNAs that are formed from inverted Alu repeats and long interspersed element (LINE) repeats located in introns and untranslated regions (UTRs) of mRNAs [6][7][8][9] . Global editing of non-coding RNA might control the expression of genes that harbour these repeat sequences of retrotransposon origin.Post-transcriptional gene regulation can also occur through RNA interference (RNAi), an evolutionarily conserved phenomenon that involves dsRNA molecules 10,11 . Small interfering RNAs (siRNAs) and microRNAs (miRNAs) are non-coding RNAs that are generated by a class of RNase III ribonucleases (specifically, Dicer and Drosha). These small RNAs are incorporated into the RNA-induced silencing complex (RISC), which mediates the RNAi process [12][13][14][15][16] . The idea that the RNAi and A→I RNA editing pathways might compete for a Competing interests statement: The author declares no competing financial interests. [23][24][25] . NIH Public AccessIn this review, I discuss recent findings on new functions of A→I RNA editing in the regulation of non...

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Identification and relative quantification of adenosine to inosine editing in serotonin 2c receptor mRNA by CE

et al. 2007

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A new method has been developed allowing the identification and relative quantification of different forms of mRNA after RNA editing. This method was applied to the serotonin 2c receptor mRNA that potentially exhibits 32 different forms after adenosine to inosine editing at five different sites located in a row of 13 nucleotides. CE was used to characterize fluorescently labeled ssDNA molecules on the basis of their conformational polymorphism. The relative amount of these 32 mRNA forms has been estimated by measuring the fluorescence intensity of each individual DNA strand. Accuracy of quantification was established by diluting one form into another or into a mixture of cDNA, showing linear and precise proportion of each form (0.06

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Regulation of Serotonin 2C Receptor Pre-mRNA Editing by Serotonin

Cited by 29 publications

References 49 publications

Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide

Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide

Editor meets silencer: crosstalk between RNA editing and RNA interference

Identification and relative quantification of adenosine to inosine editing in serotonin 2c receptor mRNA by CE

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