Journal article
Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties
Nature Communications, Vol.9(957), pp.1-15
2018
PMCID: PMC5840332
PMID: 29511171
Appears in UniSC Supported Open Access Outputs
Abstract
Genetic and bioinformatic analyses have identified missense mutations in GRIN2B encoding the NMDA receptor GluN2B subunit in autism, intellectual disability, Lennox Gastaut and West Syndromes. Here, we investigated several such mutations using a near-complete, hybrid 3D model of the human NMDAR and studied their consequences with kinetic modelling and electrophysiology. The mutants revealed reductions in glutamate potency; increased receptor desensitisation; and ablation of voltage-dependent Mg2+ block. In addition, we provide new views on Mg2+ and NMDA channel blocker binding sites. We demonstrate that these mutants have significant impact on excitatory transmission in developing neurons, revealing profound changes that could underlie their associated neurological disorders. Of note, the NMDAR channel mutant GluN2BV618G unusually allowed Mg2+ permeation, whereas nearby N615I reduced Ca2+ permeability. By identifying the binding site for an NMDAR antagonist that is used in the clinic to rescue gain-of-function phenotypes, we show that drug binding may be modified by some GluN2B disease-causing mutations.
Details
- Title
- Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties
- Authors
- Laura Fedele (Author) - UCL School of Pharmacy, United KingdomJoseph Newcombe (Author) - University of London, United KingdomMaya Topf (Author) - University of London, United KingdomAlasdair Gibb (Author) - Physiology & Pharmacology UCL, United KingdomRobert J Harvey (Author) - University of the Sunshine Coast - Faculty of Science, Health, Education and EngineeringTrevor G Smart (Author) - Physiology & Pharmacology UCL, United Kingdom
- Publication details
- Nature Communications, Vol.9(957), pp.1-15
- Publisher
- Nature Publishing Group
- Date published
- 2018
- DOI
- 10.1038/s41467-018-02927-4
- ISSN
- 2041-1723
- PMID
- 29511171; PMC5840332
- Copyright note
- Copyright © The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Organisation Unit
- School of Health; School of Health and Sport Sciences - Legacy; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
- Language
- English
- Record Identifier
- 99450656202621
- Output Type
- Journal article
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- Domestic collaboration
- International collaboration
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- Neurosciences
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