Inhibitory Action of Antidepressants on Mouse Betaine/GABA Transporter (BGT1) Heterologously Expressed in Cell Cultures

Gerile Gerile,Takashi Masuko,Katsuya Morita,Tadashi Kusama,Shigeo Kitayama,Chiharu Sogawa,Kazumi Ohyama,Norio Sogawa

doi:10.3390/ijms13032578

Gerile Gerile, Takashi Masuko + Show 6 more

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https://doi.org/10.3390/ijms13032578

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Abstract

Betaine/γ-aminobutyric acid (GABA) transporter (BGT1, SLC6A12) is a member of the Na+- and Cl−-dependent neurotransmitter transporter gene family with a homology to the GABA transporters (GATs), GAT1 (SLC6A1), GAT2 (SLC6A13) and GAT3 (SLC6A11) (HUGO nomenclature). Since antidepressants have been reported to inhibit GABA uptake, we examined those effects on mouse BGT1 (mBGT1) in comparison with other mouse GAT (mGAT) subtypes in the heterologously expressed cell cultures. All antidepressants tested here inhibited the [3H]GABA uptake through mBGT1 and mGATs in a rank order of potency with mBGT1 > mGAT1-3. Kinetic analyses for maprotilline, mianserine and trimipramine revealed that they inhibited mBGT1 and mGAT1 noncompetitively, except that mianserine competitively inhibited mBGT1. These results provided a clue to investigate the structure-function relationship of mBGT1 using antidepressants as a tool, leading to the identification of potential candidates for selective and specific inhibitors of mBGT1.

Highlights

Uptake of neurotransmitters through the plasma membrane transporter is a primary mechanism regulating extracellular neurotransmitter concentrations, thereby play a key role in the control of synaptic neurotransmission [1]
GAT1 and BGT1, it was of interest to investigate the effects of tricyclic antidepressant (TCA) on BGT1 in comparison with other GABA transporters (GATs) family. We addressed this issue by analyzing the potency of various TCA in inhibiting mouse BGT1 (mBGT1) in comparison with other GAT subtypes using [3H]GABA uptake assays in the cell cultures heterologously expressing mouse GAT subtypes
Since TCAs have been reported to inhibit GABA uptake [13], we examined those effects on mBGT1 in comparison with other mouse GAT subtypes in the heterologous expression systems

Summary

Introduction

Uptake of neurotransmitters through the plasma membrane transporter is a primary mechanism regulating extracellular neurotransmitter concentrations, thereby play a key role in the control of synaptic neurotransmission [1]. Betaine/γ-aminobutyric acid (GABA) transporter (BGT1, SLC6A12) [2,3]. Since GABA is the major inhibitory neurotransmitter in the mammalian central nervous system, GATs could be an attractive target for therapy of CNS disorders associated with GABAergic system, such as epilepsy and neuropathic pain [6,7]. Recent observations demonstrated a functional role of mouse BGT (mBGT1) or mGAT2 [8] in the control of neuronal excitability and suggested a possible utility of BGT1-selective inhibitors for the treatment of epilepsy [9]. In contrast to the known selective ligands for GAT1, for example, tiagabine known as a drug used clinically for treatment of partial seizure of epilepsy, no selective ligands for the other three GAT subtypes have been reported so far

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Discussion

Conclusion