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Glycine-dependent activation of NMDA receptors

N-methyl-d-aspartate (NMDA) receptors are the only neurotransmitter receptors whose activation requires two distinct agonists. Heterotetramers of two GluN1 and two GluN2 subunits, NMDA receptors are broadly distributed in the central nervous system, where they mediate excitatory currents in response...

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Autores principales: Cummings, Kirstie A., Popescu, Gabriela K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442789/
https://www.ncbi.nlm.nih.gov/pubmed/25964432
http://dx.doi.org/10.1085/jgp.201411302
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author Cummings, Kirstie A.
Popescu, Gabriela K.
author_facet Cummings, Kirstie A.
Popescu, Gabriela K.
author_sort Cummings, Kirstie A.
collection PubMed
description N-methyl-d-aspartate (NMDA) receptors are the only neurotransmitter receptors whose activation requires two distinct agonists. Heterotetramers of two GluN1 and two GluN2 subunits, NMDA receptors are broadly distributed in the central nervous system, where they mediate excitatory currents in response to synaptic glutamate release. Pore opening depends on the concurrent presence of glycine, which modulates the amplitude and time course of the glutamate-elicited response. Gating schemes for fully glutamate- and glycine-bound NMDA receptors have been described in sufficient detail to bridge the gap between microscopic and macroscopic receptor behaviors; for several receptor isoforms, these schemes include glutamate-binding steps. We examined currents recorded from cell-attached patches containing one GluN1/GluN2A receptor in the presence of several glycine-site agonists and used kinetic modeling of these data to develop reaction schemes that include explicit glycine-binding steps. Based on the ability to match a series of experimentally observed macroscopic behaviors, we propose a model for activation of the glutamate-bound NMDA receptor by glycine that predicts apparent negative agonist cooperativity and glycine-dependent desensitization in the absence of changes in microscopic binding or desensitization rate constants. These results complete the basic steps of an NMDA receptor reaction scheme for the GluN1/GluN2A isoform and prompt a reevaluation of how glycine controls NMDA receptor activation. We anticipate that our model will provide a useful quantitative instrument to further probe mechanisms and structure–function relationships of NMDA receptors and to better understand the physiological and pathological implications of endogenous fluctuations in extracellular glycine concentrations.
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spelling pubmed-44427892015-12-01 Glycine-dependent activation of NMDA receptors Cummings, Kirstie A. Popescu, Gabriela K. J Gen Physiol Research Articles N-methyl-d-aspartate (NMDA) receptors are the only neurotransmitter receptors whose activation requires two distinct agonists. Heterotetramers of two GluN1 and two GluN2 subunits, NMDA receptors are broadly distributed in the central nervous system, where they mediate excitatory currents in response to synaptic glutamate release. Pore opening depends on the concurrent presence of glycine, which modulates the amplitude and time course of the glutamate-elicited response. Gating schemes for fully glutamate- and glycine-bound NMDA receptors have been described in sufficient detail to bridge the gap between microscopic and macroscopic receptor behaviors; for several receptor isoforms, these schemes include glutamate-binding steps. We examined currents recorded from cell-attached patches containing one GluN1/GluN2A receptor in the presence of several glycine-site agonists and used kinetic modeling of these data to develop reaction schemes that include explicit glycine-binding steps. Based on the ability to match a series of experimentally observed macroscopic behaviors, we propose a model for activation of the glutamate-bound NMDA receptor by glycine that predicts apparent negative agonist cooperativity and glycine-dependent desensitization in the absence of changes in microscopic binding or desensitization rate constants. These results complete the basic steps of an NMDA receptor reaction scheme for the GluN1/GluN2A isoform and prompt a reevaluation of how glycine controls NMDA receptor activation. We anticipate that our model will provide a useful quantitative instrument to further probe mechanisms and structure–function relationships of NMDA receptors and to better understand the physiological and pathological implications of endogenous fluctuations in extracellular glycine concentrations. The Rockefeller University Press 2015-06 /pmc/articles/PMC4442789/ /pubmed/25964432 http://dx.doi.org/10.1085/jgp.201411302 Text en © 2015 Cummings and Popescu This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Cummings, Kirstie A.
Popescu, Gabriela K.
Glycine-dependent activation of NMDA receptors
title Glycine-dependent activation of NMDA receptors
title_full Glycine-dependent activation of NMDA receptors
title_fullStr Glycine-dependent activation of NMDA receptors
title_full_unstemmed Glycine-dependent activation of NMDA receptors
title_short Glycine-dependent activation of NMDA receptors
title_sort glycine-dependent activation of nmda receptors
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442789/
https://www.ncbi.nlm.nih.gov/pubmed/25964432
http://dx.doi.org/10.1085/jgp.201411302
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