The pathogenic S688Y mutation in the ligand-binding domain of the GluN1 subunit regulates the properties of NMDA receptors

0538934 - ÚEM 2021 RIV GB eng J - Journal Article
Skřenková, Kristýna - Song, JM. - Kortus, Štěpán - Kolcheva, Marharyta - Netolický, Jakub - Hemelíková, Katarína - Kaniaková, Martina - Hrčka Krausová, Barbora - Kučera, T. - Korábečný, J. - Suh, Y. H. - Horák, Martin
The pathogenic S688Y mutation in the ligand-binding domain of the GluN1 subunit regulates the properties of NMDA receptors.
Scientific Reports. Roč. 10, č. 1 (2020), č. článku 18576. ISSN 2045-2322. E-ISSN 2045-2322
R&D Projects: GA ČR(CZ) GA20-12420S; GA MZd(CZ) NU20-08-00296
Institutional support: RVO:68378041
Keywords : methyl-d-aspartate * glutamate receptors * surface expression
OECD category: Pharmacology and pharmacy
Impact factor: 4.380, year: 2020
Method of publishing: Open access
https://www.nature.com/articles/s41598-020-75646-w

Although numerous pathogenic mutations have been identified in various subunits of N-methyl-D-aspartate receptors (NMDARs), ionotropic glutamate receptors that are central to glutamatergic neurotransmission, the functional effects of these mutations are often unknown. Here, we combined in silico modelling with microscopy, biochemistry, and electrophysiology in cultured HEK293 cells and hippocampal neurons to examine how the pathogenic missense mutation S688Y in the GluN1 NMDAR subunit affects receptor function and trafficking. We found that the S688Y mutation significantly increases the EC50 of both glycine and d-serine in GluN1/GluN2A and GluN1/GluN2B receptors, and significantly slows desensitisation of GluN1/GluN3A receptors. Moreover, the S688Y mutation reduces the surface expression of GluN3A-containing NMDARs in cultured hippocampal neurons, but does not affect the trafficking of GluN2-containing receptors. Finally, we found that the S688Y mutation reduces Ca2+ influx through NMDARs and reduces NMDA-induced excitotoxicity in cultured hippocampal neurons. These findings provide key insights into the molecular mechanisms that underlie the regulation of NMDAR subtypes containing pathogenic mutations.
Permanent Link: http://hdl.handle.net/11104/0316668