Distinct regulation of early trafficking of the NMDA receptors by the ligand-binding domains of the GluN1 and GluN2A subunits

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378041%3A_____%2F25%3A00635656" target="_blank" >RIV/68378041:_____/25:00635656 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00179906:_____/25:10499930 RIV/00216208:11310/25:10499930 RIV/61989592:15640/25:73631351 RIV/61989100:27740/25:10258700

Výsledek na webu

<a href="https://www.jneurosci.org/content/early/2025/05/23/JNEUROSCI.0226-24.2025" target="_blank" >https://www.jneurosci.org/content/early/2025/05/23/JNEUROSCI.0226-24.2025</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1523/JNEUROSCI.0226-24.2025" target="_blank" >10.1523/JNEUROSCI.0226-24.2025</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Distinct regulation of early trafficking of the NMDA receptors by the ligand-binding domains of the GluN1 and GluN2A subunits

Popis výsledku v původním jazyce

N-methyl-D-aspartate receptors (NMDARs) play a crucial role in excitatory neurotransmission, with numerous pathogenic variants identified in the GluN subunits, including their ligand-binding domains (LBDs). The prevailing hypothesis postulates that the endoplasmic reticulum (ER) quality control machinery verifies the agonist occupancy of NMDARs, but this was tested in a limited number of studies. Using microscopy and electrophysiology in the HEK293 cells, we found that surface expression of GluN1/GluN2A receptors containing a set of alanine substitutions within the LBDs correlated with the measured EC50 values for glycine (GluN1 subunit mutations), while did not correlate with the measured EC50 values for L-glutamate (GluN2A subunit mutations). The mutant cycle of GluN1-S688 residue, including the pathogenic GluN1-S688Y and GluN1-S688P variants, showed a correlation between relative surface expression of the GluN1/GluN2A receptors and the measured EC50 values for glycine, as well as with the calculated ΔGbinding values for glycine obtained from molecular dynamics (MD) simulations. In contrast, the mutant cycle of GluN2A-S511 residue did not show any correlation between the relative surface expression of the GluN1/GluN2A receptors and the measured EC50 values for L-glutamate or calculated ΔGbinding values for L-glutamate. Co-expression of both mutated GluN1 and GluN2A subunits led to additive or synergistic alterations in the surface number of GluN1/GluN2A receptors. The synchronized ER release by ARIAD technology confirmed the altered early trafficking of GluN1/GluN2A receptors containing the mutated LBDs. The microscopical analysis from embryonal rat hippocampal neurons (both sexes) corroborated our conclusions from the HEK293 cells.

Název v anglickém jazyce

Distinct regulation of early trafficking of the NMDA receptors by the ligand-binding domains of the GluN1 and GluN2A subunits

Popis výsledku anglicky

N-methyl-D-aspartate receptors (NMDARs) play a crucial role in excitatory neurotransmission, with numerous pathogenic variants identified in the GluN subunits, including their ligand-binding domains (LBDs). The prevailing hypothesis postulates that the endoplasmic reticulum (ER) quality control machinery verifies the agonist occupancy of NMDARs, but this was tested in a limited number of studies. Using microscopy and electrophysiology in the HEK293 cells, we found that surface expression of GluN1/GluN2A receptors containing a set of alanine substitutions within the LBDs correlated with the measured EC50 values for glycine (GluN1 subunit mutations), while did not correlate with the measured EC50 values for L-glutamate (GluN2A subunit mutations). The mutant cycle of GluN1-S688 residue, including the pathogenic GluN1-S688Y and GluN1-S688P variants, showed a correlation between relative surface expression of the GluN1/GluN2A receptors and the measured EC50 values for glycine, as well as with the calculated ΔGbinding values for glycine obtained from molecular dynamics (MD) simulations. In contrast, the mutant cycle of GluN2A-S511 residue did not show any correlation between the relative surface expression of the GluN1/GluN2A receptors and the measured EC50 values for L-glutamate or calculated ΔGbinding values for L-glutamate. Co-expression of both mutated GluN1 and GluN2A subunits led to additive or synergistic alterations in the surface number of GluN1/GluN2A receptors. The synchronized ER release by ARIAD technology confirmed the altered early trafficking of GluN1/GluN2A receptors containing the mutated LBDs. The microscopical analysis from embryonal rat hippocampal neurons (both sexes) corroborated our conclusions from the HEK293 cells.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Neuroscience

ISSN

0270-6474

e-ISSN

1529-2401

Svazek periodika

45

Číslo periodika v rámci svazku

26

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

24

Strana od-do

e0226242025

Kód UT WoS článku

001524033600010

EID výsledku v databázi Scopus

2-s2.0-105009260847