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

Authors :
Dmitry A. Sibarov
Sergei I. Boikov
Tatiana V. Karelina
Sergei M. Antonov
Source :
Biomolecules, Vol 10, Iss 10, p 1441 (2020)
Publication Year :
2020
Publisher :
MDPI AG, 2020.

Abstract

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 Ca2+, we study dithiothreitol (DTT) effects on currents and Ca2+ 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 Ca2+ 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.

Details

Language :
English
ISSN :
2218273X
Volume :
10
Issue :
10
Database :
Directory of Open Access Journals
Journal :
Biomolecules
Publication Type :
Academic Journal
Accession number :
edsdoj.11fa8d42a72546e79bfb015caaa97582
Document Type :
article
Full Text :
https://doi.org/10.3390/biom10101441