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The Extracellular Domains of GluN Subunits Play an Essential Role in Processing NMDA Receptors in the ER

N-methyl-D-aspartate receptors (NMDARs) belong to a family of ionotropic glutamate receptors that play essential roles in excitatory neurotransmission and synaptic plasticity in the mammalian central nervous system (CNS). Functional NMDARs consist of heterotetramers comprised of GluN1, GluN2A-D, and...

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Autores principales: Horak, Martin, Barackova, Petra, Langore, Emily, Netolicky, Jakub, Rivas-Ramirez, Paula, Rehakova, Kristyna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007919/
https://www.ncbi.nlm.nih.gov/pubmed/33796003
http://dx.doi.org/10.3389/fnins.2021.603715
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author Horak, Martin
Barackova, Petra
Langore, Emily
Netolicky, Jakub
Rivas-Ramirez, Paula
Rehakova, Kristyna
author_facet Horak, Martin
Barackova, Petra
Langore, Emily
Netolicky, Jakub
Rivas-Ramirez, Paula
Rehakova, Kristyna
author_sort Horak, Martin
collection PubMed
description N-methyl-D-aspartate receptors (NMDARs) belong to a family of ionotropic glutamate receptors that play essential roles in excitatory neurotransmission and synaptic plasticity in the mammalian central nervous system (CNS). Functional NMDARs consist of heterotetramers comprised of GluN1, GluN2A-D, and/or GluN3A-B subunits, each of which contains four membrane domains (M1 through M4), an intracellular C-terminal domain, a large extracellular N-terminal domain composed of the amino-terminal domain and the S1 segment of the ligand-binding domain (LBD), and an extracellular loop between M3 and M4, which contains the S2 segment of the LBD. Both the number and type of NMDARs expressed at the cell surface are regulated at several levels, including their translation and posttranslational maturation in the endoplasmic reticulum (ER), intracellular trafficking via the Golgi apparatus, lateral diffusion in the plasma membrane, and internalization and degradation. This review focuses on the roles played by the extracellular regions of GluN subunits in ER processing. Specifically, we discuss the presence of ER retention signals, the integrity of the LBD, and critical N-glycosylated sites and disulfide bridges within the NMDAR subunits, each of these steps must pass quality control in the ER in order to ensure that only correctly assembled NMDARs are released from the ER for subsequent processing and trafficking to the surface. Finally, we discuss the effect of pathogenic missense mutations within the extracellular domains of GluN subunits with respect to ER processing of NMDARs.
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spelling pubmed-80079192021-03-31 The Extracellular Domains of GluN Subunits Play an Essential Role in Processing NMDA Receptors in the ER Horak, Martin Barackova, Petra Langore, Emily Netolicky, Jakub Rivas-Ramirez, Paula Rehakova, Kristyna Front Neurosci Neuroscience N-methyl-D-aspartate receptors (NMDARs) belong to a family of ionotropic glutamate receptors that play essential roles in excitatory neurotransmission and synaptic plasticity in the mammalian central nervous system (CNS). Functional NMDARs consist of heterotetramers comprised of GluN1, GluN2A-D, and/or GluN3A-B subunits, each of which contains four membrane domains (M1 through M4), an intracellular C-terminal domain, a large extracellular N-terminal domain composed of the amino-terminal domain and the S1 segment of the ligand-binding domain (LBD), and an extracellular loop between M3 and M4, which contains the S2 segment of the LBD. Both the number and type of NMDARs expressed at the cell surface are regulated at several levels, including their translation and posttranslational maturation in the endoplasmic reticulum (ER), intracellular trafficking via the Golgi apparatus, lateral diffusion in the plasma membrane, and internalization and degradation. This review focuses on the roles played by the extracellular regions of GluN subunits in ER processing. Specifically, we discuss the presence of ER retention signals, the integrity of the LBD, and critical N-glycosylated sites and disulfide bridges within the NMDAR subunits, each of these steps must pass quality control in the ER in order to ensure that only correctly assembled NMDARs are released from the ER for subsequent processing and trafficking to the surface. Finally, we discuss the effect of pathogenic missense mutations within the extracellular domains of GluN subunits with respect to ER processing of NMDARs. Frontiers Media S.A. 2021-03-16 /pmc/articles/PMC8007919/ /pubmed/33796003 http://dx.doi.org/10.3389/fnins.2021.603715 Text en Copyright © 2021 Horak, Barackova, Langore, Netolicky, Rivas-Ramirez and Rehakova. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Horak, Martin
Barackova, Petra
Langore, Emily
Netolicky, Jakub
Rivas-Ramirez, Paula
Rehakova, Kristyna
The Extracellular Domains of GluN Subunits Play an Essential Role in Processing NMDA Receptors in the ER
title The Extracellular Domains of GluN Subunits Play an Essential Role in Processing NMDA Receptors in the ER
title_full The Extracellular Domains of GluN Subunits Play an Essential Role in Processing NMDA Receptors in the ER
title_fullStr The Extracellular Domains of GluN Subunits Play an Essential Role in Processing NMDA Receptors in the ER
title_full_unstemmed The Extracellular Domains of GluN Subunits Play an Essential Role in Processing NMDA Receptors in the ER
title_short The Extracellular Domains of GluN Subunits Play an Essential Role in Processing NMDA Receptors in the ER
title_sort extracellular domains of glun subunits play an essential role in processing nmda receptors in the er
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007919/
https://www.ncbi.nlm.nih.gov/pubmed/33796003
http://dx.doi.org/10.3389/fnins.2021.603715
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