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

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.

Unveiling the crucial role of betaine: Modulation of GABA homeostasis via SLC6A1 transporter (GAT1)

“…The detailed analysis of the PSS currents gives information about the initial steps of the transporter cycle and the interaction of the transporter with ions and substrate [22]. The analysis of the decay time constant (τ) of the large transient currents as inrate β and outrate α constants showed that in the presence of betaine (0.1 and 1mM), β of rGAT1 increased.…”

“…Interestingly, it has been published that betaine might interact with the GABAergic pathway beyond BGT-1 and play a role as a signalling ligand in the CNS [19][20][21]. To investigate the potential modulatory role of betaine, we studied its interaction with GABA transporter 1 (GAT1, slc6a1) [22]. The expression of GAT1 is mainly neuronal, predominantly in the adult frontal cortex, and among all GATs it is the most expressed GAT in the CNS.…”

Unveiling the crucial role of betaine: Modulation of GABA homeostasis via SLC6A1 transporter (GAT1)

“…The detailed analysis of the PSS currents gives information about the initial steps of the transporter cycle and the interaction of the transporter with ions and substrate [22]. The analysis of the decay time constant (τ) of the large transient currents as outrate α and inrate β constants showed that in the presence of betaine (0.1 and 1mM), β of rGAT1 increased.…”

“…Interestingly, it has been reported that betaine might interact with the GABAergic pathway beyond BGT-1 and play a role as a signalling ligand in the CNS [19][20][21]. To investigate the potential modulatory role of betaine, we studied its interaction with GABA transporter 1 (GAT1, slc6a1) [22]. The expression of GAT1 is mainly neuronal, predominantly in the adult frontal cortex, and among all GATs it is the most expressed GAT in the CNS.…”

Bile acid interactions with neurotransmitter transporters

“…It is also closely related to GAT1 (GABA Transporter SLC6A1) and glycine transporters (SLC6A5 and SLC6A9), which belong to the same neurotransmitter and amino acid transporter family ( Castagna et al, 2022 ) and regulate, with other transporters of the family, the homeostasis of the two inhibitory neurotransmitters. These two transporters have been well characterized and studied for their electrical properties by our group ( Pérez-Siles et al, 2012 ; Bhatt et al, 2023 ). Furthermore, they elicit larger transport currents than DAT when expressed in Xenopus laevis oocytes.…”