Altered Editing of Serotonin 2C Receptor Pre-mRNA in the Prefrontal Cortex of Depressed Suicide Victims

Gurevich, Ilona; Tamir, Hadassah; Arango, Victoria; Dwork, Andrew J.; Mann, J. John; Schmauss, Claudia

doi:10.1016/s0896-6273(02)00660-8

Cited by 353 publications

(297 citation statements)

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“…As was mentioned in the Introduction section, three different laboratories have previously reported changes in the 5-HT 2C R mRNA editing in the PFC of suicide victims. [12][13][14] Niswender et al 12 looked at editing at the A, C and D sites in patients with SZ, MDD and in normal controls. No differences between diagnostic and control groups were found, but secondary analyses comparing suicides to all non-suicides or to non-suicides with SZ or MDD, identified increases in editing at the A site with a trend toward an increase in editing at the D site in the latter comparison.…”

Section: Discussionmentioning

confidence: 99%

“…They reported trends for increased D site editing in MDD and increased A site editing in those patients who committed suicide. Gurevich et al 13 compared suicides with a history of MDD to controls. That study had a very limited scope, but it analyzed all five editing sites.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have suggested abnormalities in mRNA editing of one of the serotonin receptors-2C (5-HT 2C R)-in depressed suicide victims. [12][13][14] 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 that either add or delete nucleotides, or that change one nucleotide into another.…”

Section: Introductionmentioning

confidence: 99%

“…[12][13][14] Those studies reported highly variable results that in general indicated increased editing in psychiatric subjects who died from suicide (see Discussion section for details). However, those studies were not designed a priori to investigate differences between the editing variations associated with suicide as opposed to those associated with psychiatric conditions.…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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“…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 . …”

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confidence: 95%

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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Serotonin Systems

Gray

Roth

2007

Handbook of Contemporary Neuropharmacology

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The serotonin (5‐HT) system is reviewed starting from the early history of 5‐HT. There is a review of the biosynthesis, degradation, and synaptic reuptake of 5‐HT as well as the neuroanatomy of the 5‐HT system. The roles of these pathways in disease and therapeutic interventions are discussed. The focus of this chapter is on the multiple 5‐HT receptors, their history, anatomical and subcellular localization, signaling pathways, and importance in behavior, neuropsychiatric disorders and psychopharmacology.

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Altered Editing of Serotonin 2C Receptor Pre-mRNA in the Prefrontal Cortex of Depressed Suicide Victims

Cited by 353 publications

References 21 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

Serotonin Systems

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