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GluN2 Subunit-Dependent Redox Modulation of NMDA Receptor Activation by Homocysteine

Homocysteine (HCY) molecule combines distinct pharmacological properties as an agonist of N-methyl-d-aspartate receptors (NMDARs) and a reducing agent. Whereas NMDAR activation by HCY was elucidated, whether the redox modulation contributes to its action is unclear. Here, using patch-clamp recording...

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Autores principales: Sibarov, Dmitry A., Boikov, Sergei I., Karelina, Tatiana V., Antonov, Sergei M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602226/
https://www.ncbi.nlm.nih.gov/pubmed/33066432
http://dx.doi.org/10.3390/biom10101441
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author Sibarov, Dmitry A.
Boikov, Sergei I.
Karelina, Tatiana V.
Antonov, Sergei M.
author_facet Sibarov, Dmitry A.
Boikov, Sergei I.
Karelina, Tatiana V.
Antonov, Sergei M.
author_sort Sibarov, Dmitry A.
collection PubMed
description Homocysteine (HCY) molecule combines distinct pharmacological properties as an agonist of N-methyl-d-aspartate receptors (NMDARs) and a reducing agent. Whereas NMDAR activation by HCY was elucidated, whether the redox modulation contributes to its action is unclear. Here, using patch-clamp recording and imaging of intracellular Ca(2+), we study dithiothreitol (DTT) effects on currents and Ca(2+) responses activated by HCY through native NMDARs and recombinant diheteromeric GluN1/2A, GluN1/2B, and GluN1/2C receptors. Within a wide range (1–800 μM) of [HCY]s, the concentration–activation relationships for recombinant NMDARs revealed a biphasicness. The high-affinity component obtained between 1 and 100 µM [HCY]s corresponding to the NMDAR activation was not affected by 1 mM DTT. The low-affinity phase observed at [HCY]s above 200 μM probably originated from thiol-dependent redox modulation of NMDARs. The reduction of NMDAR disulfide bonds by either 1 mM DTT or 1 mM HCY decreased GluN1/2A currents activated by HCY. In contrast, HCY-elicited GluN1/2B currents were enhanced due to the remarkable weakening of GluN1/2B desensitization. In fact, cleaving NMDAR disulfide bonds in neurons reversed the HCY-induced Ca(2+) accumulation, making it dependent on GluN2B- rather than GluN2A-containing NMDARs. Thus, estimated concentrations for the HCY redox effects exceed those in the plasma during intermediate hyperhomocysteinemia but may occur during severe hyperhomocysteinemia.
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spelling pubmed-76022262020-11-01 GluN2 Subunit-Dependent Redox Modulation of NMDA Receptor Activation by Homocysteine Sibarov, Dmitry A. Boikov, Sergei I. Karelina, Tatiana V. Antonov, Sergei M. Biomolecules Article Homocysteine (HCY) molecule combines distinct pharmacological properties as an agonist of N-methyl-d-aspartate receptors (NMDARs) and a reducing agent. Whereas NMDAR activation by HCY was elucidated, whether the redox modulation contributes to its action is unclear. Here, using patch-clamp recording and imaging of intracellular Ca(2+), we study dithiothreitol (DTT) effects on currents and Ca(2+) responses activated by HCY through native NMDARs and recombinant diheteromeric GluN1/2A, GluN1/2B, and GluN1/2C receptors. Within a wide range (1–800 μM) of [HCY]s, the concentration–activation relationships for recombinant NMDARs revealed a biphasicness. The high-affinity component obtained between 1 and 100 µM [HCY]s corresponding to the NMDAR activation was not affected by 1 mM DTT. The low-affinity phase observed at [HCY]s above 200 μM probably originated from thiol-dependent redox modulation of NMDARs. The reduction of NMDAR disulfide bonds by either 1 mM DTT or 1 mM HCY decreased GluN1/2A currents activated by HCY. In contrast, HCY-elicited GluN1/2B currents were enhanced due to the remarkable weakening of GluN1/2B desensitization. In fact, cleaving NMDAR disulfide bonds in neurons reversed the HCY-induced Ca(2+) accumulation, making it dependent on GluN2B- rather than GluN2A-containing NMDARs. Thus, estimated concentrations for the HCY redox effects exceed those in the plasma during intermediate hyperhomocysteinemia but may occur during severe hyperhomocysteinemia. MDPI 2020-10-14 /pmc/articles/PMC7602226/ /pubmed/33066432 http://dx.doi.org/10.3390/biom10101441 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sibarov, Dmitry A.
Boikov, Sergei I.
Karelina, Tatiana V.
Antonov, Sergei M.
GluN2 Subunit-Dependent Redox Modulation of NMDA Receptor Activation by Homocysteine
title GluN2 Subunit-Dependent Redox Modulation of NMDA Receptor Activation by Homocysteine
title_full GluN2 Subunit-Dependent Redox Modulation of NMDA Receptor Activation by Homocysteine
title_fullStr GluN2 Subunit-Dependent Redox Modulation of NMDA Receptor Activation by Homocysteine
title_full_unstemmed GluN2 Subunit-Dependent Redox Modulation of NMDA Receptor Activation by Homocysteine
title_short GluN2 Subunit-Dependent Redox Modulation of NMDA Receptor Activation by Homocysteine
title_sort glun2 subunit-dependent redox modulation of nmda receptor activation by homocysteine
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602226/
https://www.ncbi.nlm.nih.gov/pubmed/33066432
http://dx.doi.org/10.3390/biom10101441
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