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Distinct Regulation of Early Trafficking of the NMDA Receptors by the Ligand-Binding Domains of the GluN1 and GluN2A Subunits
J. Netolicky, P. Zahumenska, A. Misiachna, M. Kolcheva, K. Rehakova, K. Hemelikova, S. Kortus, E. Langore, J. Doderovic, M. Ladislav, J. Korabecny, M. Otyepka, M. Srejber, M. Horak
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
NLK
Free Medical Journals
od 1981 do Před 6 měsíci
PubMed Central
od 1981 do Před 6 měsíci
Europe PubMed Central
od 1981 do Před 6 měsíci
Open Access Digital Library
od 1981-01-01
Open Access Digital Library
od 1981-01-01
- MeSH
- glycin metabolismus MeSH
- HEK293 buňky MeSH
- hipokampus cytologie metabolismus MeSH
- krysa rodu rattus MeSH
- kyselina glutamová metabolismus MeSH
- lidé MeSH
- ligandy MeSH
- mutace genetika MeSH
- proteinové domény MeSH
- proteiny nervové tkáně MeSH
- receptory N-methyl-D-aspartátu * metabolismus genetika chemie MeSH
- transport proteinů fyziologie genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
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 human embryonic kidney 293 (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 not correlating 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 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. Coexpression 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.
Department of Physiology Faculty of Science Charles University Prague Prague 12843 Czech Republic
IT4Innovations VSB Technical University of Ostrava Ostrava Poruba 708 00 Czech Republic
Citace poskytuje Crossref.org
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