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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
Language English Country United States
Document type Journal Article
NLK
Free Medical Journals
from 1981 to 6 months ago
PubMed Central
from 1981 to 6 months ago
Europe PubMed Central
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Open Access Digital Library
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- MeSH
- Glycine metabolism MeSH
- HEK293 Cells MeSH
- Hippocampus cytology metabolism MeSH
- Rats MeSH
- Glutamic Acid metabolism MeSH
- Humans MeSH
- Ligands MeSH
- Mutation genetics MeSH
- Protein Domains MeSH
- Nerve Tissue Proteins MeSH
- Receptors, N-Methyl-D-Aspartate * metabolism genetics chemistry MeSH
- Protein Transport physiology genetics MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article 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
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