In:
eLife, eLife Sciences Publications, Ltd, Vol. 10 ( 2021-07-02)
Abstract:
The N-methyl-D-aspartate receptors (NMDARs; GluNRS) are glutamate receptors, commonly located at excitatory synapses. Mutations affecting receptor function often lead to devastating neurodevelopmental disorders. We have identified two toddlers with different heterozygous missense mutations of the same, and highly conserved, glycine residue located in the ligand-binding-domain of GRIN2B : G689C and G689S. Structure simulations suggest severely impaired glutamate binding, which we confirm by functional analysis. Both variants show three orders of magnitude reductions in glutamate EC 50 , with G689S exhibiting the largest reductions observed for GRIN2B (~2000-fold). Moreover, variants multimerize with, and upregulate, GluN2B wt -subunits, thus engendering a strong dominant-negative effect on mixed channels. In neurons, overexpression of the variants instigates suppression of synaptic GluNRs. Lastly, while exploring spermine potentiation as a potential treatment, we discovered that the variants fail to respond due to G689’s novel role in proton-sensing. Together, we describe two unique variants with extreme effects on channel function. We employ protein-stability measures to explain why current (and future) LBD mutations in GluN2B primarily instigate Loss-of-Function.
Type of Medium:
Online Resource
ISSN:
2050-084X
Language:
English
Publisher:
eLife Sciences Publications, Ltd
Publication Date:
2021
detail.hit.zdb_id:
2687154-3
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