RNA editing (R/G site) and flip–flop splicing of the AMPA receptor subunit GluR2 in nervous tissue of epilepsy patients

Vollmar, W.R.; Gloger, J; Berger, Eva; Kortenbruck, G; Köhling, Rüdiger; Speckmann, E.‐J.; Mußhoff, Ulrich

doi:10.1016/j.nbd.2003.11.006

Cited by 65 publications

(46 citation statements)

References 34 publications

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“…Several investigations have associated altered recoding levels in specific sites with various neurological and neurodegenerative disorders Vissel et al 2001;Maas et al 2006;Tariq and Jantsch 2012;Slotkin and Nishikura 2013;Gaisler-Salomon et al 2014;Li et al 2014), such as major depression, epilepsy, schizophrenia, amyotrophic lateral sclerosis, and Alzheimer's disease (Feldmeyer et al 1999;Kortenbruck et al 2001;Vollmar et al 2004;Iwamoto et al 2005Iwamoto et al , 2009). However, so far, only a small fraction of recoding sites has been characterized and investigated in a pathological context.…”

Section: Introductionmentioning

confidence: 99%

Reduced levels of protein recoding by A-to-I RNA editing in Alzheimer's disease

Khermesh

D’Erchia

Barák

et al. 2015

RNA

132

110

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Adenosine to inosine (A-to-I) RNA editing, catalyzed by the ADAR enzyme family, acts on dsRNA structures within pre-mRNA molecules. Editing of the coding part of the mRNA may lead to recoding, amino acid substitution in the resulting protein, possibly modifying its biochemical and biophysical properties. Altered RNA editing patterns have been observed in various neurological pathologies. Here, we present a comprehensive study of recoding by RNA editing in Alzheimer's disease (AD), the most common cause of irreversible dementia. We have used a targeted resequencing approach supplemented by a microfluidic-based high-throughput PCR coupled with next-generation sequencing to accurately quantify A-to-I RNA editing levels in a preselected set of target sites, mostly located within the coding sequence of synaptic genes. Overall, editing levels decreased in AD patients' brain tissues, mainly in the hippocampus and to a lesser degree in the temporal and frontal lobes. Differential RNA editing levels were observed in 35 target sites within 22 genes. These results may shed light on a possible association between the neurodegenerative processes typical for AD and deficient RNA editing.

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Section: Introductionmentioning

confidence: 99%

Reduced levels of protein recoding by A-to-I RNA editing in Alzheimer's disease

Khermesh

D’Erchia

Barák

et al. 2015

RNA

132

110

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“…A number of recent studies reported editing changes in pathological human brain tissues. Editing at GluR2 R/G sites is increased in hippocampal tissue of epileptic patients (Vollmar et al 2004). Decrease in GluR2 Q/R site editing was found in motoneurons of patients with amyotrophic lateral sclerosis (Kwak and Kawahara 2005;Kawahara et al 2004) and in malignant brain tumors (Maas et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Editing of AMPA and Serotonin 2C Receptors in Individual Central Neurons, Controlling Wakefulness

2007

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(1) Pre-mRNA editing of serotonin 2C (5-HT2c) and glutamate (Glu) receptors (R) influences higher brain functions and pathological states such as epilepsy, amyotrophic lateral sclerosis, and depression. Adenosine deaminases acting on RNA (ADAR1-3) convert adenosine to inosine on synthetic RNAs, analogous to 5-HT2cR and GluR. The order of editing as well as mechanisms controlling editing in native neurons is unknown. (2) With single-cell RT-PCR we investigated the co-expression of ADAR genes with GluR and 5-HT2cR and determined the editing status at known sites in the hypothalamic tuberomamillary nucleus, a major center for wakefulness and arousal. (3) The most frequently expressed enzymes were ADAR1, followed by ADAR2. The Q/R site of GluR2 was always fully edited. Editing at the R/G site in the GluR2 (but not GluR4) subunit was co-ordinated with ADAR expression: maximal editing was found in neurons expressing both ADAR2 splice variants of the deaminase domain and lacking ADAR3. (4) Editing of the 5-HT2cR did not correlate with ADAR expression. The 5-HT2cR mRNA was always edited at A, in the majority of cells at B sites and variably edited at E, C and D sites. A negative correlation was found between editing of C and D sites. The GluR4 R/G site editing was homogeneous within individuals: it was fully edited in all neurons obtained from 12 rats and under-edited in six neurons obtained from three rats. (5) We conclude that GluR2 R/G editing is controlled at the level of ADAR2 and therefore this enzyme may be a target for pharmacotherapy. On the other hand, further factors/enzymes besides ADAR must control or influence 5-HT2cR and GluR pre-mRNA editing in native neurons; our data indicate that these factors vary between individuals and could be predictors of psychiatric disease.

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“…5 Altered editing at the Q/R site of both GluA2 and GluK2 has also been implicated in epilepsy. 21,22 In addition, editing of another neurotransmitter receptor, the serotonin 2C receptor (5-HT 2C R), has been implicated in schizophrenia, depression and suicide. [23][24][25][26][27][28] However, editing in iGluRs has never been comprehensively assessed in the human brain in the context of psychiatric conditions within the same brain region.…”

Section: Introductionmentioning

confidence: 99%

Ionotropic glutamate receptor mRNA editing in the prefrontal cortex: no alterations in schizophrenia or bipolar disorder

Lyddon

Navarrett²,

Dracheva³

2012

jpn

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IntroductionGlutamate is the main neurotransmitter responsible for excitatory neurotransmission throughout the brain. Glutamate serves as a ligand for G-protein coupled metabotropic and ionotropic (iGluRs) receptors. The latter consists of N-methyl-D-aspartate, α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and kainate (KA) subtypes. Glutamate dysfunction has been linked to numerous diseases, including schizophrenia, bipolar disorder and major depressive disorder. 1-6The AMPA and KA receptors are ligand-gated nonselective cation channels that mediate fast excitatory neurotransmission. Each receptor is a tetramer composed of a combination of subunits encoded by separate genes, GluA1-4 for AMPA, and GluK1-3 and KA1-2 for KA receptors. Individual subunit transcripts undergo posttranscriptional modifications that substantially alter the structure and function of the resulting receptors. Alternative splicing of GluA1-4 generates 2 different variants of each subunit (flip or flop), forming AMPA receptors with distinct kinetic properties. [7][8][9] In addition, AMPA and KA receptor transcripts can be modified by RNA editing. 10The most frequent RNA editing process in eukaryotes involves conversion of adenosine to inosine catalyzed by the adenosine deaminases acting on RNA (ADAR) enzymes.11 As inosine is interpreted as a guanosine during splicing and translation, the editing event can result in recoding. A total of Background: Dysfunction of glutamate neurotransmission has been implicated in the pathology of schizophrenia and bipolar disorder, and one mechanism by which glutamate signalling can be altered is through RNA editing of ionotropic glutamate receptors (iGluRs). The objectives of the present study were to evaluate the editing status of iGluRs in the human prefrontal cortex, determine whether iGluR editing is associated with psychiatric disease or suicide and evaluate a potential association between editing and alternative splicing in the α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) iGluR subunits' pre-mRNA. Methods: We studied specimens derived from patients with antemortem diagnoses of bipolar disorder (n = 31) or schizophrenia (n = 34) who died by suicide or other causes, and from psychiatrically healthy controls (n = 34) who died from causes other than suicide. The RNA editing at all 8 editing sites within AMPA (GluA2-4 subunits) and kainate (GluK1-2 subunits) iGluRs was analyzed using a novel real-time quantitative polymerase chain reaction assay. Results: No differences in editing were detected among schizophrenia, bipolar or control groups or between suicide completers and patients who died from causes other than suicide. The editing efficiency was significantly higher in the flop than in the flip splicoforms of GluA3-4 AMPA subunits (all p < 0.001). Limitations: The study is limited by the near absence of specimens from medicationnaive psychiatric patients and considerable variation in medication regimens among individuals, both of which introduce considerable uncertainty into the ana...

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RNA editing (R/G site) and flip–flop splicing of the AMPA receptor subunit GluR2 in nervous tissue of epilepsy patients

Cited by 65 publications

References 34 publications

Reduced levels of protein recoding by A-to-I RNA editing in Alzheimer's disease

Reduced levels of protein recoding by A-to-I RNA editing in Alzheimer's disease

Editing of AMPA and Serotonin 2C Receptors in Individual Central Neurons, Controlling Wakefulness

Ionotropic glutamate receptor mRNA editing in the prefrontal cortex: no alterations in schizophrenia or bipolar disorder

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