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-...
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| Format: | Article |
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Frontiers Media S.A.
2023-04-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2023.1145973/full |
| _version_ | 1797847606370500608 |
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| author | Manan Bhatt Manan Bhatt Laure Gauthier-Manuel Erika Lazzarin Rocco Zerlotti Rocco Zerlotti Christine Ziegler Andre Bazzone Thomas Stockner Elena Bossi Elena Bossi |
| author_facet | Manan Bhatt Manan Bhatt Laure Gauthier-Manuel Erika Lazzarin Rocco Zerlotti Rocco Zerlotti Christine Ziegler Andre Bazzone Thomas Stockner Elena Bossi Elena Bossi |
| author_sort | Manan Bhatt |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-09T18:14:09Z |
| format | Article |
| id | doaj.art-122f346d4f684060bcd6969a55da141f |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-04-09T18:14:09Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-122f346d4f684060bcd6969a55da141f2023-04-13T05:03:09ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2023-04-011410.3389/fphys.2023.11459731145973A comparative review on the well-studied GAT1 and the understudied BGT-1 in the brainManan Bhatt0Manan Bhatt1Laure Gauthier-Manuel2Erika Lazzarin3Rocco Zerlotti4Rocco Zerlotti5Christine Ziegler6Andre Bazzone7Thomas Stockner8Elena Bossi9Elena Bossi10Department of Biotechnology and Life Sciences, University of Insubria, Varese, ItalyCentre for Neuroscience—University of Insubria, Varese, ItalyDepartment of Biophysics II/Structural Biology, University of Regensburg, Regensburg, GermanyCenter for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Waehringerstr, ViennaDepartment of Biophysics II/Structural Biology, University of Regensburg, Regensburg, GermanyNanion Technologies GmbH, Munich, GermanyDepartment of Biophysics II/Structural Biology, University of Regensburg, Regensburg, GermanyNanion Technologies GmbH, Munich, GermanyCenter for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Waehringerstr, ViennaDepartment of Biotechnology and Life Sciences, University of Insubria, Varese, ItalyCentre for Neuroscience—University of Insubria, Varese, Italyγ-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.https://www.frontiersin.org/articles/10.3389/fphys.2023.1145973/fullGABAtransporterSLC6 neurotransmitter transportersGAT1BGT-1structure-function |
| spellingShingle | Manan Bhatt Manan Bhatt Laure Gauthier-Manuel Erika Lazzarin Rocco Zerlotti Rocco Zerlotti Christine Ziegler Andre Bazzone Thomas Stockner Elena Bossi Elena Bossi A comparative review on the well-studied GAT1 and the understudied BGT-1 in the brain Frontiers in Physiology GABA transporter SLC6 neurotransmitter transporters GAT1 BGT-1 structure-function |
| 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 | GABA transporter SLC6 neurotransmitter transporters GAT1 BGT-1 structure-function |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2023.1145973/full |
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