Role of the Ion Channel Extracellular Collar in AMPA Receptor Gating

Abstract AMPA subtype ionotropic glutamate receptors mediate fast excitatory neurotransmission and are implicated in numerous neurological diseases. Ionic currents through AMPA receptor channels can be allosterically regulated via different sites on the receptor protein. We used site-directed mutage...

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Auteurs principaux:	Maria V. Yelshanskaya, Samaneh Mesbahi-Vasey, Maria G. Kurnikova, Alexander I. Sobolevsky
Format:	article
Langue:	EN
Publié:	Nature Portfolio 2017
Sujets:	Medicine R Science Q
Accès en ligne:	https://doaj.org/article/14345d29ccd34d319f88edb0585b7c09
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id	oai:doaj.org-article:14345d29ccd34d319f88edb0585b7c09
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spelling	oai:doaj.org-article:14345d29ccd34d319f88edb0585b7c092021-12-02T12:32:00ZRole of the Ion Channel Extracellular Collar in AMPA Receptor Gating10.1038/s41598-017-01146-z2045-2322https://doaj.org/article/14345d29ccd34d319f88edb0585b7c092017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01146-zhttps://doaj.org/toc/2045-2322Abstract AMPA subtype ionotropic glutamate receptors mediate fast excitatory neurotransmission and are implicated in numerous neurological diseases. Ionic currents through AMPA receptor channels can be allosterically regulated via different sites on the receptor protein. We used site-directed mutagenesis and patch-clamp recordings to probe the ion channel extracellular collar, the binding region for noncompetitive allosteric inhibitors. We found position and substitution-dependent effects for introduced mutations at this region on AMPA receptor gating. The results of mutagenesis suggested that the transmembrane domains M1, M3 and M4, which contribute to the ion channel extracellular collar, undergo significant relative displacement during gating. We used molecular dynamics simulations to predict an AMPA receptor open state structure and rationalize the results of mutagenesis. We conclude that the ion channel extracellular collar plays a distinct role in gating and represents a hub for powerful allosteric modulation of AMPA receptor function that can be used for developing novel therapeutics.Maria V. YelshanskayaSamaneh Mesbahi-VaseyMaria G. KurnikovaAlexander I. SobolevskyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maria V. Yelshanskaya Samaneh Mesbahi-Vasey Maria G. Kurnikova Alexander I. Sobolevsky Role of the Ion Channel Extracellular Collar in AMPA Receptor Gating
description	Abstract AMPA subtype ionotropic glutamate receptors mediate fast excitatory neurotransmission and are implicated in numerous neurological diseases. Ionic currents through AMPA receptor channels can be allosterically regulated via different sites on the receptor protein. We used site-directed mutagenesis and patch-clamp recordings to probe the ion channel extracellular collar, the binding region for noncompetitive allosteric inhibitors. We found position and substitution-dependent effects for introduced mutations at this region on AMPA receptor gating. The results of mutagenesis suggested that the transmembrane domains M1, M3 and M4, which contribute to the ion channel extracellular collar, undergo significant relative displacement during gating. We used molecular dynamics simulations to predict an AMPA receptor open state structure and rationalize the results of mutagenesis. We conclude that the ion channel extracellular collar plays a distinct role in gating and represents a hub for powerful allosteric modulation of AMPA receptor function that can be used for developing novel therapeutics.
format	article
author	Maria V. Yelshanskaya Samaneh Mesbahi-Vasey Maria G. Kurnikova Alexander I. Sobolevsky
author_facet	Maria V. Yelshanskaya Samaneh Mesbahi-Vasey Maria G. Kurnikova Alexander I. Sobolevsky
author_sort	Maria V. Yelshanskaya
title	Role of the Ion Channel Extracellular Collar in AMPA Receptor Gating
title_short	Role of the Ion Channel Extracellular Collar in AMPA Receptor Gating
title_full	Role of the Ion Channel Extracellular Collar in AMPA Receptor Gating
title_fullStr	Role of the Ion Channel Extracellular Collar in AMPA Receptor Gating
title_full_unstemmed	Role of the Ion Channel Extracellular Collar in AMPA Receptor Gating
title_sort	role of the ion channel extracellular collar in ampa receptor gating
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/14345d29ccd34d319f88edb0585b7c09
work_keys_str_mv	AT mariavyelshanskaya roleoftheionchannelextracellularcollarinampareceptorgating AT samanehmesbahivasey roleoftheionchannelextracellularcollarinampareceptorgating AT mariagkurnikova roleoftheionchannelextracellularcollarinampareceptorgating AT alexanderisobolevsky roleoftheionchannelextracellularcollarinampareceptorgating
_version_	1718394202736295936

Role of the Ion Channel Extracellular Collar in AMPA Receptor Gating

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