A comparative review on the well-studied GAT1 and the understudied BGT-1 in the brain

Manan Bhatt; Laure Gauthier-Manuel; Erika Lazzarin; Rocco Zerlotti; Christine Ziegler; Andre Bazzone; Thomas Stockner; Elena Bossi

doi:10.3389/fphys.2023.1145973

A comparative review on the well-studied GAT1 and the understudied BGT-1 in the brain

Front Physiol. 2023 Apr 13:14:1145973. doi: 10.3389/fphys.2023.1145973. eCollection 2023.

Authors

Manan Bhatt^{1

2}, Laure Gauthier-Manuel³, Erika Lazzarin⁴, Rocco Zerlotti^{3

5}, Christine Ziegler³, Andre Bazzone⁵, Thomas Stockner⁴, Elena Bossi^{1

2}

Affiliations

¹ Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy.
² Centre for Neuroscience-University of Insubria, Varese, Italy.
³ Department of Biophysics II/Structural Biology, University of Regensburg, Regensburg, Germany.
⁴ Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Waehringerstr, Vienna.
⁵ Nanion Technologies GmbH, Munich, Germany.

Abstract

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.

Keywords: BGT-1; GABA; GAT1; SLC6 neurotransmitter transporters; structure-function; transporter.

Publication types

Review

Grants and funding

This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 860954 to AB, EB, TS, and CZ.