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Last update 23 Jan 2025

BGT1

Last update 23 Jan 2025

Basic Info

Synonyms

betaine/GABA transporter-1, BGT-1, Na(+)/Cl(-) betaine/GABA transporter

+ [5]

Introduction

Transports betaine and GABA. May have a role in regulation of GABAergic transmission in the brain through the reuptake of GABA into presynaptic terminals, as well as in osmotic regulation.

Drugs associated with BGT1

SBV2-114

Target

BGT1

Mechanism

BGT1 inhibitors

Active Org.

University of Copenhagen

Originator Org.

University of Copenhagen

Active Indication

Seizures

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

NNC-052090

Target

BGT1 x GABA transporter subfamily

Mechanism

BGT1 inhibitors [+1]

Active Org.

Novo Nordisk A/S

Originator Org.

Novo Nordisk A/S

Active Indication

Epilepsy

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

SBV-114

Target

BGT1

Mechanism

BGT1 inhibitors

Active Org.-

Originator Org.

University of Copenhagen

Active Indication-

Inactive Indication

Epilepsy

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with BGT1

100 Translational Medicine associated with BGT1

0 Patents (Medical) associated with BGT1

223

Literatures (Medical) associated with BGT1

01 Jan 2025·Laboratory Investigation

Cefadroxil Targeting of SLC15A2/PEPT2 Protects From Colistin Nephrotoxicity

Article

Author: Valiño, Lara ; Sanz, Ana B ; Pintor-Chocano, Aranzazu ; Sanchez-Niño, Maria Dolores ; Fernandez-Prado, Raul ; Sanz, Ana B. ; Ortiz, Alberto

Acute kidney injury (AKI) and chronic kidney disease (CKD) are considered interconnected syndromes, as AKI episodes may accelerate CKD progression, and CKD increases the risk of AKI. Genome-wide association studies (GWAS) may identify novel actionable therapeutic targets. Human GWAS for AKI or CKD were combined with murine AKI transcriptomics data sets to identify 13 (ACACB, ACSM5, CNDP1, DPEP1, GATM, SLC6A12, AGXT2L1, SLC15A2, CTSS, ICAM1, ITGAX, ITGAM, and PPM1J) potentially actionable therapeutic targets to modulate kidney disease severity across species and the AKI-CKD spectrum. Among them, SLC15A2, encoding the cell membrane proton-coupled peptide transporter 2, was prioritized for data mining and functional intervention studies in vitro and in vivo because of its known function to transport nephrotoxic drugs such as colistin and the possibility for targeting with small molecules already in clinical use, such as cefadroxil. Data mining disclosed that SLC15A2 was upregulated in the tubulointerstitium of human CKD, including diabetic nephropathy, and the upregulation was localized to proximal tubular cells. Colistin elicited cytotoxicity and proinflammatory response in cultured human and murine proximal tubular cells that was decreased by concomitant exposure to cefadroxil. In proof-of-concept in vivo studies, cefadroxil protected from colistin nephrotoxicity in mice. The GWAS association of SLC15A2 with human kidney disease may be actionable and related to the modifiable transport of nephrotoxins causing repeated subclinical episodes of AKI and/or chronic nephrotoxicity.

01 Dec 2024·Developmental Cell

The de novo synthesis of GABA and its gene regulatory function control hepatocellular carcinoma metastasis

Article

Author: Li, Li ; Liu, Fangming ; Kou, Junjie ; Li, Wei ; Du, Wenjing ; Zhang, Zhenxi ; Cheng, Running ; He, Xiaojing ; Liu, Zizhao ; Zhao, Haitao ; Wu, Fujia ; Kang, Youli

The neurotransmitter gamma-aminobutyric acid (GABA) has been thought to be involved in the development of some types of cancer. Yet, the de novo synthesis of GABA and how it functions in hepatocellular carcinoma (HCC) remain unclear. Here, we report that SLC6A12 acts as a transporter of GABA, and that aldehyde dehydrogenase 9 family member A1 (ALDH9A1), not glutamate decarboxylase 1 (GAD1), generates GABA in human HCC. Interestingly, SLC6A12 and ALDH9A1 are upregulated during lung metastases of HCC, and depletion of either of them leads to impaired HCC metastasis. Mechanistically, GABA directly binds and stabilizes β-catenin, resulting in activated Wnt/β-catenin signaling, and thereby enhancing HCC metastasis. Reciprocally, β-catenin transcriptionally upregulates SLC6A12 to import more GABA to stabilize β-catenin. Thus, our findings identify ALDH9A1 as the major GABA synthetase in HCC, demonstrate a positive-feedback regulatory mechanism for sustaining Wnt/β-catenin signaling, and reveal a role for β-catenin in sensing GABA, which contributes to HCC metastasis.

06 Nov 2024·ACS Chemical Neuroscience

Rational Search for Betaine/GABA Transporter 1 Inhibitors─In Vitro Evaluation of Selected Hit Compound

Article

Author: Siwek, Agata ; Zaręba, Paula ; Bajda, Marek ; Rzepka, Zuzanna ; Łątka, Kamil ; Latacz, Gniewomir ; Wellendorph, Petrine ; Kickinger, Stefanie ; Wolak, Małgorzata ; Stary, Dorota ; Marcinkowska, Monika ; Wrześniok, Dorota

Inhibitory neurotransmission mediated by γ-aminobutyric acid (GABA) plays an important role in maintaining body homeostasis. Disturbances in GABA signaling are implicated in a multitude of neurologic and psychiatric conditions, including epilepsy, ischemia, anxiety, depression, insomnia, and mood disorders. Clinically relevant increases in GABA neurotransmitter level can be achieved by inhibition of its uptake into presynaptic neurons and surrounding glial cells, driven by GABA transporters (GAT1, BGT1, GAT2, and GAT3). Herein, we focused on the search for inhibitors of the BGT1 transporter which is understudied and for which the therapeutic potential of its inhibition is partly unknown. We applied multilevel virtual screening to identify compounds with inhibitory properties. Among selected hits, compound 9 was shown to be a preferential inhibitor of BGT1 (IC₅₀ 13.9 μM). The compound also revealed some inhibitory activity against GAT3 (4x lower) while showing no or low activity (IC₅₀ > 100 μM) toward GAT1 and GAT2, respectively. The predicted binding mode of compound 9 was confirmed by mutagenesis studies on E52A, E52Y, Q299L, and E52A+Q299L human BGT1 mutants. Subsequent evaluation showed that the selected hit displayed no affinity toward major GABA_A receptor subtypes. Moreover, it was nontoxic when tested on normal human astrocytes and even showed some neuroprotective activity in SH-SY5Y cells. Compound 9 is considered a promising candidate for further evaluation of the therapeutic potential of BGT1 transporter inhibition and the development of novel inhibitors.

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BGT1

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