Disease relevance of SLC6A12

• Gamma-aminobutyric acid transporter (BGT-1) expressed in human astrocytoma U373 MG cells: pharmacological and molecular characterization and phorbol ester-induced inhibition [1].

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 1.1.1.21), 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

• The data show that human peripheral blood monocytes and human peripheral blood-derived macrophages use betaine and myoinositol are compatible organic osmolytes when exposed to osmotic stress and that p38MAPK is involved in hyperosmolarity-induced upregulation of osmolyte transporters BGT-1 and SMIT [7].
• Hyperosmotic (405 mOsm) exposure of monocytes and macrophages led to an upregulation of betaine/gamma-amino-n-butyric acid (GABA) transporter BGT-1 and sodium-dependent myoinositol transporter SMIT in mRNA levels within 6 to 12 h [7].
• These results suggest that the BGT-1 isoform may be functionally expressed by rat calvarial osteoblasts to play a hitherto unidentified role in mechanisms underlying hyperosmotic regulation of osteoblastogenesis [9].
• Highly immunoreactive cells were detected for the BGT-1 isoform at the surface of trabecular bone of neonatal rat tibias [9].
• BGT-1 was observed in pyramidal neurons in the cerebral neocortex and the CA fields of the hippocampus [10].

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

• Role of the betaine/GABA transporter (BGT-1/GAT2) for the control of epilepsy [15].

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].

References