Glycine Transporter 2: Mechanism and Allosteric Modulation

Neurotransmitter sodium symporters (NSS) are a subfamily of SLC6 transporters responsible for regulating neurotransmitter signalling. They are a major target for psychoactive substances including antidepressants and drugs of abuse, prompting substantial research into their modulation and structure-f...

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Autores principales:	Zachary J. Frangos, Ryan P. Cantwell Chater, Robert J. Vandenberg
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	glycine transporter allosteric modulation solute carrier 6 (SLC6) neurotransmitter sodium symporters (NSS) lipid modulation Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/59be87d5f5c9496f8c74f204583d012a
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spelling	oai:doaj.org-article:59be87d5f5c9496f8c74f204583d012a2021-11-05T10:58:24ZGlycine Transporter 2: Mechanism and Allosteric Modulation2296-889X10.3389/fmolb.2021.734427https://doaj.org/article/59be87d5f5c9496f8c74f204583d012a2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fmolb.2021.734427/fullhttps://doaj.org/toc/2296-889XNeurotransmitter sodium symporters (NSS) are a subfamily of SLC6 transporters responsible for regulating neurotransmitter signalling. They are a major target for psychoactive substances including antidepressants and drugs of abuse, prompting substantial research into their modulation and structure-function dynamics. Recently, a series of allosteric transport inhibitors have been identified, which may reduce side effect profiles, compared to orthosteric inhibitors. Allosteric inhibitors are also likely to provide different clearance kinetics compared to competitive inhibitors and potentially better clinical outcomes. Crystal structures and homology models have identified several allosteric modulatory sites on NSS including the vestibule allosteric site (VAS), lipid allosteric site (LAS) and cholesterol binding site (CHOL1). Whilst the architecture of eukaryotic NSS is generally well conserved there are differences in regions that form the VAS, LAS, and CHOL1. Here, we describe ligand-protein interactions that stabilize binding in each allosteric site and explore how differences between transporters could be exploited to generate NSS specific compounds with an emphasis on GlyT2 modulation.Zachary J. FrangosRyan P. Cantwell ChaterRobert J. VandenbergFrontiers Media S.A.articleglycine transporterallosteric modulationsolute carrier 6 (SLC6)neurotransmitter sodium symporters (NSS)lipid modulationBiology (General)QH301-705.5ENFrontiers in Molecular Biosciences, Vol 8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	glycine transporter allosteric modulation solute carrier 6 (SLC6) neurotransmitter sodium symporters (NSS) lipid modulation Biology (General) QH301-705.5
spellingShingle	glycine transporter allosteric modulation solute carrier 6 (SLC6) neurotransmitter sodium symporters (NSS) lipid modulation Biology (General) QH301-705.5 Zachary J. Frangos Ryan P. Cantwell Chater Robert J. Vandenberg Glycine Transporter 2: Mechanism and Allosteric Modulation
description	Neurotransmitter sodium symporters (NSS) are a subfamily of SLC6 transporters responsible for regulating neurotransmitter signalling. They are a major target for psychoactive substances including antidepressants and drugs of abuse, prompting substantial research into their modulation and structure-function dynamics. Recently, a series of allosteric transport inhibitors have been identified, which may reduce side effect profiles, compared to orthosteric inhibitors. Allosteric inhibitors are also likely to provide different clearance kinetics compared to competitive inhibitors and potentially better clinical outcomes. Crystal structures and homology models have identified several allosteric modulatory sites on NSS including the vestibule allosteric site (VAS), lipid allosteric site (LAS) and cholesterol binding site (CHOL1). Whilst the architecture of eukaryotic NSS is generally well conserved there are differences in regions that form the VAS, LAS, and CHOL1. Here, we describe ligand-protein interactions that stabilize binding in each allosteric site and explore how differences between transporters could be exploited to generate NSS specific compounds with an emphasis on GlyT2 modulation.
format	article
author	Zachary J. Frangos Ryan P. Cantwell Chater Robert J. Vandenberg
author_facet	Zachary J. Frangos Ryan P. Cantwell Chater Robert J. Vandenberg
author_sort	Zachary J. Frangos
title	Glycine Transporter 2: Mechanism and Allosteric Modulation
title_short	Glycine Transporter 2: Mechanism and Allosteric Modulation
title_full	Glycine Transporter 2: Mechanism and Allosteric Modulation
title_fullStr	Glycine Transporter 2: Mechanism and Allosteric Modulation
title_full_unstemmed	Glycine Transporter 2: Mechanism and Allosteric Modulation
title_sort	glycine transporter 2: mechanism and allosteric modulation
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/59be87d5f5c9496f8c74f204583d012a
work_keys_str_mv	AT zacharyjfrangos glycinetransporter2mechanismandallostericmodulation AT ryanpcantwellchater glycinetransporter2mechanismandallostericmodulation AT robertjvandenberg glycinetransporter2mechanismandallostericmodulation
_version_	1718444290816868352

Glycine Transporter 2: Mechanism and Allosteric Modulation

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