Fedele, L;
Newcombe, J;
Topf, M;
Gibb, A;
Harvey, RJ;
Smart, TG;
(2018)
Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties.
Nature Communications
, 9
, Article 957. 10.1038/s41467-018-02927-4.
Preview |
Text (Published article)
s41467-018-02927-4.pdf - Published Version Download (2MB) | Preview |
Preview |
Text (Supplementary information)
Fedele_Disease-associated_missense_mutations_Suppl.pdf Download (2MB) | Preview |
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 GluN2BV618Gunusually 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.
| Type: | Article |
|---|---|
| Title: | Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41467-018-02927-4 |
| Publisher version: | http://dx.doi.org/10.1038/s41467-018-02927-4 |
| Language: | English |
| Additional information: | 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/. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10045506 |
Archive Staff Only
 |
View Item |
