ADAR2-mediated Q/R editing of GluK2 regulates kainate receptor upscaling in response to suppression of synaptic activity
Open accessPublished version of a preprint
Abstract
Kainate receptors (KARs) regulate neuronal excitability and network function. Most KARs contain the subunit GluK2 (also known as GRIK2), and the properties of these receptors are determined in part by ADAR2 (also known as ADARB1)-mediated mRNA editing of GluK2, which changes a genomically encoded glutamine residue into an arginine residue (Q/R editing). Suppression of synaptic activity reduces ADAR2-dependent Q/R editing of GluK2 with a consequential increase in GluK2-containing KAR surface expression. However, the mechanism underlying this reduction in GluK2 editing has not been addressed. Here, we show that induction of KAR upscaling, a phenomenon in which surface expression of receptors is increased in response to a chronic decrease in synaptic activity, results in proteasomal degradation of ADAR2, which reduces GluK2 Q/R editing. Because KARs incorporating unedited GluK2(Q) assemble and exit the ER more efficiently, this leads to an upscaling of KAR surface expression. Consistent with this, we demonstrate that partial ADAR2 knockdown phenocopies and occludes KAR upscaling. Moreover, we show that although the AMPA receptor (AMPAR) subunit GluA2 (also known as GRIA2) also undergoes ADAR2-dependent Q/R editing, this process does not mediate AMPAR upscaling. These data demonstrate that activity-dependent regulation of ADAR2 proteostasis and GluK2 Q/R editing are key determinants of KAR, but not AMPAR, trafficking and upscaling.This article has an associated First Person interview with the first author of the paper.
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In BM36, altered A-to-I editing sites include GRIA2 (R/G and Q/R), GRIK2 (Q/R), and NOVA1 (S/G).
“For example, in BM36, we identified well characterized A-to-I editing sites of GRIA2 (R/G and Q/R) (55, 75, 76) and GRIK2 (Q/R) (29, 77), as well as previously reported editing sites in NOVA1 (S/G) (29, 56) (Fig. 5D).”
From Comprehensive characterization of the transcriptional landscape in Alzheimer’s disease (AD) brains (2025) · cites this paper as [77]
The Results section, “Suppression of synaptic activity decreases ADAR2 levels” (page unavailable), reports GluK2/GRIK2 Q/R editing, supporting that editing-site identification. The cited paper does not address NOVA1 S/G editing, although it is also cited for that site. The BM36 finding is presented as the citing authors’ own result, not as a finding from this source. (LLM, conf=0.86)
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- Authors
- Gurung, S., Evans, A. J., Wilkinson, K. A., & Henley, J. M.
- Affiliations
- University of Bristol (GB)
- Corresponding author
- Henley, Jeremy M.
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2018-12-15
- Volume
- 131
- Issue
- 24
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- PMC
- PMC6307878
- OpenAlex
- W2898020275
- Cited by
- 26
- References
- 41
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 1 · 2022: 4 · 2021: 6 · 2020: 3 · 2019: 1 · 2018: 1
- FWCI
- 1.25
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- www.biologists.com/user-licence-1-1/ (vor)
- Locations
- Journal of Cell Science (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion, other-oa)
- Explore Bristol Research (acceptedVersion, other-oa)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Wellcome Trust
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- ADAR2, GluK2, kainate receptors, synaptic activity, proteasomal degradation, AMPA receptors, GluA2, receptor trafficking, endoplasmic reticulum, activity-dependent regulation, RNA editing
- MeSH terms
- GluK2 Kainate Receptor, Adenosine Deaminase, Animals, RNA-Binding Proteins, Rats, Wistar, RNA Editing, Receptors, AMPA, Kainic Acid Receptors, Receptors, Kainic Acid, Protein Transport
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