Developmental Modulation of GABAA Receptor Function by RNA Editing

Rula, Elizabeth Y.; Lagrange, Andre H.; Jacobs, Michelle M.; Hu, Ningning; Macdonald, Robert L.; Emeson, Ronald B.

doi:10.1523/jneurosci.0443-08.2008

Cited by 90 publications

(112 citation statements)

References 29 publications

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“…Editing at the I/M Site of Gabra-3 Is Developmentally Regulated-We and others have previously shown that editing at the I/M site of Gabra-3 increases with age (4,21,23). It is also known that the ␣3 protein decreases during brain development (12).…”

Section: Resultsmentioning

confidence: 99%

Adenosine-to-Inosine RNA Editing Affects Trafficking of the γ-Aminobutyric Acid Type A (GABAA) Receptor

Daniel

Wahlstedt

Ohlson

et al. 2011

Journal of Biological Chemistry

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Recoding by adenosine-to-inosine RNA editing plays an important role in diversifying proteins involved in neurotransmission. We have previously shown that the Gabra-3 transcript, coding for the ␣3 subunit of the GABA A receptor is edited in mouse, causing an isoleucine to methionine (I/M) change. Here we show that this editing event is evolutionarily conserved from human to chicken. Analyzing recombinant GABA A receptor subunits expressed in HEK293 cells, our results suggest that editing at the I/M site in ␣3 has functional consequences on receptor expression. We demonstrate that I/M editing reduces the cell surface and the total number of ␣3 subunits. The reduction in cell surface levels is independent of the subunit combination as it is observed for ␣3 in combination with either the ␤2 or the ␤3 subunit. Further, an amino acid substitution at the corresponding I/M site in the ␣1 subunit has a similar effect on cell surface presentation, indicating the importance of this site for receptor trafficking. We show that the I/M editing during brain development is inversely related to the ␣3 protein abundance. Our results suggest that editing controls trafficking of ␣3-containing receptors and may therefore facilitate the switch of subunit compositions during development as well as the subcellular distribution of ␣ subunits in the adult brain. Adenosine to inosine (A-to-I)2 RNA editing is a mechanism used in the mammalian nervous system to provide alterations in the protein sequence by co-transcriptional modification of single nucleotides. This modification is catalyzed by adenosine deaminases that act on RNA (ADAR1 and ADAR2) that can selectively modify adenosine to inosine residues within double stranded pre-mRNAs. Within mRNA transcripts, inosine is read as guanosine by the translation machinery. Therefore, this mechanism has the potential to change the amino acid sequence and thereby the function of the protein. Several gene products encoding proteins involved in neurotransmission have been shown to be A-to-I edited, including ligand-and voltage-gated ion channels as well as a G-proteincoupled receptor and thereby creating diverse isoforms of proteins essential for balanced neuronal kinetics (reviewed in Ref. 1).One of the most well studied substrates for editing in the brain is the transcript coding for the AMPA glutamate receptor (GluA). AMPA receptors consist of four subunits (GluA1-GluA4) in different combinations. Changing a codon for glutamine to arginine in GluA2 is essential to the organism and required for a normal brain development (2, 3).We have previously found that the mouse Gabra-3 transcript, coding for the ␣3 subunit of the GABA A receptor undergoes site-selective A-to-I editing causing an isoleucine to methionine (I/M) change in the third transmembrane region (TM3) (4). The chloride-permeable (GABA A ) receptors are the main mediators of fast inhibitory neurotransmission in the mammalian central nervous system (reviewed in Ref. 5). These heteropentameric ligand-gated chloride ion channels can be f...

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Section: Resultsmentioning

confidence: 99%

Adenosine-to-Inosine RNA Editing Affects Trafficking of the γ-Aminobutyric Acid Type A (GABAA) Receptor

Daniel

Wahlstedt

Ohlson

et al. 2011

Journal of Biological Chemistry

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“…Editing at the R/G site in the subunits of the glutamate receptor and the I/V site of the voltage-gated potassium channel Kcna1 results in functions that influence the kinetics of the receptors that are suitable for the mature brain. It has recently been suggested that editing of the alpha3 transcript Gabra3 results in receptors with slower activation and faster deactivation rates (Rula et al 2008). However, it is not known what effects this might have on the GABA A receptor in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Also, in the transcript of the human KCNA1 channel, an isoleucine codon is changed upon editing, but here the edited ITT codon is recognized as a valine (Bhalla et al 2004). Editing of both Gabra3 and KCNA1 has been suggested to have functional consequences on the receptors (Bhalla et al 2004;Rula et al 2008). The editing enzyme ADARB1 edits its own premRNA within intron 4 to induce alternative splicing (Rueter et al 1999).…”

mentioning

confidence: 99%

Large-scale mRNA sequencing determines global regulation of RNA editing during brain development

Wahlstedt¹,

Daniel²,

Ensterö³

et al. 2009

Genome Res.

276

304

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RNA editing by adenosine deamination has been shown to generate multiple isoforms of several neural receptors, often with profound effects on receptor function. However, little is known about the regulation of editing activity during development. We have developed a large-scale RNA sequencing protocol to determine adenosine-to-inosine (A-to-I) editing frequencies in the coding region of genes in the mammalian brain. Using the 454 Life Sciences (Roche) Amplicon Sequencing technology, we were able to determine even low levels of editing with high accuracy. The efficiency of editing for 28 different sites was analyzed during the development of the mouse brain from embryogenesis to adulthood. We show that, with few exceptions, the editing efficiency is low during embryogenesis, increasing gradually at different rates up to the adult mouse. The variation in editing gave receptors like HTR2C and GABA A (gamma-aminobutyric acid type A) a different set of protein isoforms during development from those in the adult animal. Furthermore, we show that this regulation of editing activity cannot be explained by an altered expression of the ADAR proteins but, rather, by the presence of a regulatory network that controls the editing activity during development.

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“…However, the second aspect is also essential, in that the extent of RNA editing readily exerts biological consequences. Importantly, alteration of editing levels during development or disease could have profound functional impacts (Paz et al 2007;Gallo and Galardi 2008;Rula et al 2008;Wahlstedt et al 2009;Silberberg et al 2012). In addition, the same issue exists in the analysis of allele-specific expression, where the allelic ratios of genetic variants in the expressed RNA need to be estimated accurately.…”

Section: Read Mapping Stringency Improves Accuracy In Estimated Rna Ementioning

confidence: 99%

Analysis and design of RNA sequencing experiments for identifying RNA editing and other single-nucleotide variants

Lee

Ang

Xiao

2013

RNA

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RNA-sequencing (RNA-Seq) technologies hold enormous promise for novel discoveries in genomics and transcriptomics. In the past year, a surge of reports has analyzed RNA-Seq data to gain a global view of the RNA editome. Opposing results have been presented, giving rise to extensive debate surrounding one of the first such studies in which a daunting list of all 12 types of RNA-DNA differences (RDDs) were identified. Although a consensus is forming that some of the initial "paradigm-shifting" results of this study may be questionable, recent reports on this topic differed in terms of the number and relative abundance of each type of RDD. Many outstanding issues exist, most importantly, the choice of bioinformatic approaches. Here we discuss the critical data analysis and experimental design issues of such studies to enable improved systematic investigation of the largely unexplored frontier of single-nucleotide variants in RNA.

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Developmental Modulation of GABAA Receptor Function by RNA Editing

Cited by 90 publications

References 29 publications

Adenosine-to-Inosine RNA Editing Affects Trafficking of the γ-Aminobutyric Acid Type A (GABAA) Receptor

Adenosine-to-Inosine RNA Editing Affects Trafficking of the γ-Aminobutyric Acid Type A (GABAA) Receptor

Large-scale mRNA sequencing determines global regulation of RNA editing during brain development

Analysis and design of RNA sequencing experiments for identifying RNA editing and other single-nucleotide variants

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