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A comparative review on the well-studied GAT1 and the understudied BGT-1 in the brain
γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system (CNS). Its homeostasis is maintained by neuronal and glial GABA transporters (GATs). The four GATs identified in humans are GAT1 (SLC6A1), GAT2 (SLC6A13), GAT3 (SLC6A11), and betaine/GABA transporter-...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10137170/ https://www.ncbi.nlm.nih.gov/pubmed/37123280 http://dx.doi.org/10.3389/fphys.2023.1145973 |
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author | Bhatt, Manan Gauthier-Manuel, Laure Lazzarin, Erika Zerlotti, Rocco Ziegler, Christine Bazzone, Andre Stockner, Thomas Bossi, Elena |
author_facet | Bhatt, Manan Gauthier-Manuel, Laure Lazzarin, Erika Zerlotti, Rocco Ziegler, Christine Bazzone, Andre Stockner, Thomas Bossi, Elena |
author_sort | Bhatt, Manan |
collection | PubMed |
description | γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system (CNS). Its homeostasis is maintained by neuronal and glial GABA transporters (GATs). The four GATs identified in humans are GAT1 (SLC6A1), GAT2 (SLC6A13), GAT3 (SLC6A11), and betaine/GABA transporter-1 BGT-1 (SLC6A12) which are all members of the solute carrier 6 (SLC6) family of sodium-dependent transporters. While GAT1 has been investigated extensively, the other GABA transporters are less studied and their role in CNS is not clearly defined. Altered GABAergic neurotransmission is involved in different diseases, but the importance of the different transporters remained understudied and limits drug targeting. In this review, the well-studied GABA transporter GAT1 is compared with the less-studied BGT-1 with the aim to leverage the knowledge on GAT1 to shed new light on the open questions concerning BGT-1. The most recent knowledge on transporter structure, functions, expression, and localization is discussed along with their specific role as drug targets for neurological and neurodegenerative disorders. We review and discuss data on the binding sites for Na(+), Cl(−), substrates, and inhibitors by building on the recent cryo-EM structure of GAT1 to highlight specific molecular determinants of transporter functions. The role of the two proteins in GABA homeostasis is investigated by looking at the transport coupling mechanism, as well as structural and kinetic transport models. Furthermore, we review information on selective inhibitors together with the pharmacophore hypothesis of transporter substrates. |
format | Online Article Text |
id | pubmed-10137170 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-101371702023-04-28 A comparative review on the well-studied GAT1 and the understudied BGT-1 in the brain Bhatt, Manan Gauthier-Manuel, Laure Lazzarin, Erika Zerlotti, Rocco Ziegler, Christine Bazzone, Andre Stockner, Thomas Bossi, Elena Front Physiol Physiology γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system (CNS). Its homeostasis is maintained by neuronal and glial GABA transporters (GATs). The four GATs identified in humans are GAT1 (SLC6A1), GAT2 (SLC6A13), GAT3 (SLC6A11), and betaine/GABA transporter-1 BGT-1 (SLC6A12) which are all members of the solute carrier 6 (SLC6) family of sodium-dependent transporters. While GAT1 has been investigated extensively, the other GABA transporters are less studied and their role in CNS is not clearly defined. Altered GABAergic neurotransmission is involved in different diseases, but the importance of the different transporters remained understudied and limits drug targeting. In this review, the well-studied GABA transporter GAT1 is compared with the less-studied BGT-1 with the aim to leverage the knowledge on GAT1 to shed new light on the open questions concerning BGT-1. The most recent knowledge on transporter structure, functions, expression, and localization is discussed along with their specific role as drug targets for neurological and neurodegenerative disorders. We review and discuss data on the binding sites for Na(+), Cl(−), substrates, and inhibitors by building on the recent cryo-EM structure of GAT1 to highlight specific molecular determinants of transporter functions. The role of the two proteins in GABA homeostasis is investigated by looking at the transport coupling mechanism, as well as structural and kinetic transport models. Furthermore, we review information on selective inhibitors together with the pharmacophore hypothesis of transporter substrates. Frontiers Media S.A. 2023-04-13 /pmc/articles/PMC10137170/ /pubmed/37123280 http://dx.doi.org/10.3389/fphys.2023.1145973 Text en Copyright © 2023 Bhatt, Gauthier-Manuel, Lazzarin, Zerlotti, Ziegler, Bazzone, Stockner and Bossi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Physiology Bhatt, Manan Gauthier-Manuel, Laure Lazzarin, Erika Zerlotti, Rocco Ziegler, Christine Bazzone, Andre Stockner, Thomas Bossi, Elena A comparative review on the well-studied GAT1 and the understudied BGT-1 in the brain |
title | A comparative review on the well-studied GAT1 and the understudied BGT-1 in the brain |
title_full | A comparative review on the well-studied GAT1 and the understudied BGT-1 in the brain |
title_fullStr | A comparative review on the well-studied GAT1 and the understudied BGT-1 in the brain |
title_full_unstemmed | A comparative review on the well-studied GAT1 and the understudied BGT-1 in the brain |
title_short | A comparative review on the well-studied GAT1 and the understudied BGT-1 in the brain |
title_sort | comparative review on the well-studied gat1 and the understudied bgt-1 in the brain |
topic | Physiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10137170/ https://www.ncbi.nlm.nih.gov/pubmed/37123280 http://dx.doi.org/10.3389/fphys.2023.1145973 |
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