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Gene Review

SLC6A12  -  solute carrier family 6 (neurotransmitter...

Homo sapiens

Synonyms: BGT-1, BGT1, GAT2, Na(+)/Cl(-) betaine/GABA transporter, Sodium-and chloride-dependent betaine transporter, ...
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Disease relevance of SLC6A12


High impact information on SLC6A12

  • High NaCl activates the transcription factor tonicity-responsive enhancer/osmotic response element-binding protein (TonEBP/OREBP), resulting in increased transcription of several protective genes, including the glycine betaine/gamma-aminobutyric acid transporter (BGT1) [2].
  • Above 330 mosmol/kg, cultured nucleus pulposus cells up-regulated target genes TauT, BGT-1, and SMIT; above 450 mosmol/kg, there was raised expression of HSP-70 [3].
  • Two representative genes are the aldose reductase enzyme (AR, EC, which is responsible for the conversion of glucose to sorbitol, and the betaine transporter (BGT1), which mediates Na+-coupled betaine uptake in response to osmotic stress [4].
  • We recently reported that the induction of BGT1 mRNA in the renal epithelial Madin-Darby canine kidney cell line is inhibited by SB203580, a specific p38 kinase inhibitor [4].
  • Rotenone and myxothiazol reduce high NaCl-induced increases in TonEBP/OREBP transcriptional activity (ORE/TonE reporter assay) and BGT1 (betaine transporter) mRNA abundance ranging from 53 to 69% [5].

Biological context of SLC6A12

  • Taken together, these results indicate that U373 MG cells express a GABA transporter of the BGT-1 subtype whose function is regulated by phosphorylation events through PKC [1].
  • The human homologue of the canine GABA/betaine transporter (BGT-1) was isolated from a kidney inner medulla cDNA library [6].
  • Betaine (5 mM) inhibited upregulation of BGT-1 as well as SMIT mRNA [7].
  • Reversal of this adaptive process, upon removal of hypertonic stress, involves a rapid efflux of betaine through specific release pathways, a reduction in betaine influx, and a slower downregulation of BGT1 protein abundance [8].
  • In response to hypertonic stress, there is transcriptional activation of the BGT1 gene, followed by trafficking and membrane insertion of BGT1 protein [8].

Anatomical context of SLC6A12


Associations of SLC6A12 with chemical compounds

  • The highest degree of amino acid identity is with a betaine/GABA transporter originally cloned from the dog termed BGT-1 (91%) and a related transporter from mouse brain (87%) [11].
  • The cloning of the human homologue of BGT-1 will further our understanding of the roles of GABA and betaine in neural function [11].
  • In this study, we identify with reverse transcription-polymerase chain reaction (RT-PCR) BGT-1 and EAAT3 as transporters for GABA and glutamate, respectively [12].
  • In vivo methylation by dimethyl sulfate reveals that the TonE site of the BGT1 gene is protected with a time course like that of activity of the TonEBPs and activation of transcription [13].
  • Moreover, TR-TBTs exhibit taurine, GABA, and DHEA-S uptake activity via TauT, BGT-1, and oatp2, respectively [14].

Other interactions of SLC6A12


Analytical, diagnostic and therapeutic context of SLC6A12

  • Northern blot analysis reveals that BGT-1 mRNA is widely distributed throughout the human brain [11].
  • Accordingly, [(3)H]GABA uptake was also inhibited by betaine, and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of total RNA from U373 MG cells with specific BGT-1 primers resulted in the amplification of a 440 bp fragment that was further characterized by restriction analysis and sequencing [1].
  • In addition, Western blot analysis with anti-BGT-1 antiserum revealed the presence of a characteristic 60 kDa band [1].
  • Gene induction profiles differed under the two stress conditions, however: quantitative polymerase chain reaction (PCR) experiments showed that AR, BGT-1 and SMIT, which encode proteins governing organic osmolyte accumulation, were induced by hypersalinity but not by desiccation [16].


  1. Gamma-aminobutyric acid transporter (BGT-1) expressed in human astrocytoma U373 MG cells: pharmacological and molecular characterization and phorbol ester-induced inhibition. Ruiz-Tachiquín, M.E., Sánchez-Lemus, E., Soria-Jasso, L.E., Arias-Montaño, J.A., Ortega, A. J. Neurosci. Res. (2002) [Pubmed]
  2. ATM, a DNA damage-inducible kinase, contributes to activation by high NaCl of the transcription factor TonEBP/OREBP. Irarrazabal, C.E., Liu, J.C., Burg, M.B., Ferraris, J.D. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  3. TonEBP/OREBP is a regulator of nucleus pulposus cell function and survival in the intervertebral disc. Tsai, T.T., Danielson, K.G., Guttapalli, A., Oguz, E., Albert, T.J., Shapiro, I.M., Risbud, M.V. J. Biol. Chem. (2006) [Pubmed]
  4. Osmotic response element enhancer activity. Regulation through p38 kinase and mitogen-activated extracellular signal-regulated kinase kinase. Nadkarni, V., Gabbay, K.H., Bohren, K.M., Sheikh-Hamad, D. J. Biol. Chem. (1999) [Pubmed]
  5. Mitochondrial reactive oxygen species contribute to high NaCl-induced activation of the transcription factor TonEBP/OREBP. Zhou, X., Ferraris, J.D., Burg, M.B. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  6. Molecular cloning and functional characterization of a GABA/betaine transporter from human kidney. Rasola, A., Galietta, L.J., Barone, V., Romeo, G., Bagnasco, S. FEBS Lett. (1995) [Pubmed]
  7. Osmolyte strategy in human monocytes and macrophages: involvement of p38MAPK in hyperosmotic induction of betaine and myoinositol transporters. Denkert, C., Warskulat, U., Hensel, F., Häussinger, D. Arch. Biochem. Biophys. (1998) [Pubmed]
  8. Osmotic regulation of renal betaine transport: transcription and beyond. Kempson, S.A., Montrose, M.H. Pflugers Arch. (2004) [Pubmed]
  9. Possible expression of a particular gamma-aminobutyric acid transporter isoform responsive to upregulation by hyperosmolarity in rat calvarial osteoblasts. Fujimori, S., Hinoi, E., Takarada, T., Iemata, M., Takahata, Y., Yoneda, Y. Eur. J. Pharmacol. (2006) [Pubmed]
  10. A light and electron microscopic study of betaine/GABA transporter distribution in the monkey cerebral neocortex and hippocampus. Zhu, X.M., Ong, W.Y. J. Neurocytol. (2004) [Pubmed]
  11. Cloning and expression of a betaine/GABA transporter from human brain. Borden, L.A., Smith, K.E., Gustafson, E.L., Branchek, T.A., Weinshank, R.L. J. Neurochem. (1995) [Pubmed]
  12. GABA and glutamate transporters are expressed in human platelets. Rainesalo, S., Keränen, T., Saransaari, P., Honkaniemi, J. Brain Res. Mol. Brain Res. (2005) [Pubmed]
  13. Cis- and trans-acting factors regulating transcription of the BGT1 gene in response to hypertonicity. Miyakawa, H., Woo, S.K., Chen, C.P., Dahl, S.C., Handler, J.S., Kwon, H.M. Am. J. Physiol. (1998) [Pubmed]
  14. Conditionally immortalized syncytiotrophoblast cell lines as new tools for study of the blood-placenta barrier. Kitano, T., Iizasa, H., Hwang, I.W., Hirose, Y., Morita, T., Maeda, T., Nakashima, E. Biol. Pharm. Bull. (2004) [Pubmed]
  15. Role of the betaine/GABA transporter (BGT-1/GAT2) for the control of epilepsy. Schousboe, A., Larsson, O.M., Sarup, A., White, H.S. Eur. J. Pharmacol. (2004) [Pubmed]
  16. Response of human cells to desiccation: comparison with hyperosmotic stress response. Huang, Z., Tunnacliffe, A. J. Physiol. (Lond.) (2004) [Pubmed]
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