A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors

Abstract NMDA receptors (NMDARs) contribute to several neuropathological processes. Novel positive allosteric modulators (PAMs) of NMDARs have recently been identified but their effects on NMDAR gating remain largely unknown. To this end, we tested the effect of a newly developed molecule UBP684 on...

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Autores principales:	Divyan A. Chopra, Kiran Sapkota, Mark W. Irvine, Guangyu Fang, David E. Jane, Daniel T. Monaghan, Shashank M. Dravid
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9f33dc1aa5444fdbaec987412ab161fc
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spelling	oai:doaj.org-article:9f33dc1aa5444fdbaec987412ab161fc2021-12-02T12:32:52ZA single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors10.1038/s41598-017-07292-82045-2322https://doaj.org/article/9f33dc1aa5444fdbaec987412ab161fc2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07292-8https://doaj.org/toc/2045-2322Abstract NMDA receptors (NMDARs) contribute to several neuropathological processes. Novel positive allosteric modulators (PAMs) of NMDARs have recently been identified but their effects on NMDAR gating remain largely unknown. To this end, we tested the effect of a newly developed molecule UBP684 on GluN1/GluN2A receptors. We found that UBP684 potentiated the whole-cell currents observed under perforated-patch conditions and slowed receptor deactivation. At the single channel level, UBP684 produced a dramatic reduction in long shut times and a robust increase in mean open time. These changes were similar to those produced by NMDAR mutants in which the ligand-binding domains (LBDs) are locked in the closed clamshell conformation by incorporating a disulfide bridge. Since the locked glutamate-binding clefts primarily contributes to receptor efficacy these results suggests that UBP684 binding may induce switch in conformation similar to glutamate LBD locked state. Consistent with this prediction UBP684 displayed greater potentiation of NMDARs with only the GluN1 LBD locked compared to NMDARs with only the GluN2 LBD locked. Docking studies suggest that UBP684 binds to the GluN1 and GluN2 LBD interface supporting its potential ability in stabilizing the LBD closed conformation. Together these studies identify a novel pharmacological mechanism of facilitating the function of NMDARs.Divyan A. ChopraKiran SapkotaMark W. IrvineGuangyu FangDavid E. JaneDaniel T. MonaghanShashank M. DravidNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Divyan A. Chopra Kiran Sapkota Mark W. Irvine Guangyu Fang David E. Jane Daniel T. Monaghan Shashank M. Dravid A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors
description	Abstract NMDA receptors (NMDARs) contribute to several neuropathological processes. Novel positive allosteric modulators (PAMs) of NMDARs have recently been identified but their effects on NMDAR gating remain largely unknown. To this end, we tested the effect of a newly developed molecule UBP684 on GluN1/GluN2A receptors. We found that UBP684 potentiated the whole-cell currents observed under perforated-patch conditions and slowed receptor deactivation. At the single channel level, UBP684 produced a dramatic reduction in long shut times and a robust increase in mean open time. These changes were similar to those produced by NMDAR mutants in which the ligand-binding domains (LBDs) are locked in the closed clamshell conformation by incorporating a disulfide bridge. Since the locked glutamate-binding clefts primarily contributes to receptor efficacy these results suggests that UBP684 binding may induce switch in conformation similar to glutamate LBD locked state. Consistent with this prediction UBP684 displayed greater potentiation of NMDARs with only the GluN1 LBD locked compared to NMDARs with only the GluN2 LBD locked. Docking studies suggest that UBP684 binds to the GluN1 and GluN2 LBD interface supporting its potential ability in stabilizing the LBD closed conformation. Together these studies identify a novel pharmacological mechanism of facilitating the function of NMDARs.
format	article
author	Divyan A. Chopra Kiran Sapkota Mark W. Irvine Guangyu Fang David E. Jane Daniel T. Monaghan Shashank M. Dravid
author_facet	Divyan A. Chopra Kiran Sapkota Mark W. Irvine Guangyu Fang David E. Jane Daniel T. Monaghan Shashank M. Dravid
author_sort	Divyan A. Chopra
title	A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors
title_short	A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors
title_full	A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors
title_fullStr	A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors
title_full_unstemmed	A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors
title_sort	single-channel mechanism for pharmacological potentiation of glun1/glun2a nmda receptors
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/9f33dc1aa5444fdbaec987412ab161fc
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A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors

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