Disease relevance of SLC6A9

• Human placental choriocarcinoma (JAR) cells endogenously expressing glycine transporter type 1a (GlyT1a) have been cultured in 96-well scintillating microplates to develop a homogenous screening assay for the detection of GlyT1 antagonists [1].

High impact information on SLC6A9

• Protein kinase C activation reduced maximum velocity for GLYT1-mediated glycine uptake without effect on the Michaelis constant [2].
• CONCLUSIONS: Enterocytes express GLYT1 along the length of the crypt-villus axis, where it mediates high-affinity basolateral glycine uptake [2].
• Consistent with these functional data, molecular techniques detected expression of GLYT1 messenger RNA and protein in the human intestine and Caco-2 cells [2].
• METHODS: Assimilation of [(14)C]glycine was studied in human enterocytic Caco-2 cells, and expression of the glycine transporter GLYT1 was examined in Caco-2 cells and human intestine by reverse-transcription polymerase chain reaction, immunoblotting, and immunohistochemistry [2].
• In this study we have investigated the actions of Zn2+ on the glycine transporters, GLYT1b and GLYT2a, expressed in Xenopus laevis oocytes and we demonstrate that Zn2+ is a noncompetitive inhibitor of GLYT1 but has no effect on GLYT2 [3].

Biological context of SLC6A9

• Assignment of SLC6A9 to human chromosome band 1p33 by in situ hybridization [4].
• We have also investigated the molecular basis for these differences and the relationship between the Zn2+ and proton binding sites on GLYT1 [3].
• Analysis of surface proteins by biotinylation and by immunofluorescence demonstrates that a significant portion of the unglycosylated GLYT1 mutant remains in the intracellular compartment [5].
• To elucidate the role of N-glycosylation in the function of the high affinity glycine transporter GLYT1, we have investigated the effect of the glycosylation inhibitor tunicamycin as well as the effect of the disruption of the putative glycosylation sites by site-directed mutagenesis [5].
• These molecules also exhibit superior pharmacological and pharmacokinetic parameters, relative to all GlyT1 inhibitors of the spiropiperidine family, culminating in the identification of 16b with an oral bioavailability of approximately 60% [6].

Anatomical context of SLC6A9

• In this study, we demonstrate that Müller cells cultured from human retinas are capable of strongly expressing the glycine transporter Glyt-1 as assessed by immunocytochemistry [7].
• This suggests that the carbohydrate moiety of glycine transporter GLYT1 is necessary for the proper trafficking of the protein to the plasma membrane [5].
• We have synthesized a potent selective inhibitor of glycine transporter 1 (GlyT1), and characterized its activity using a quail fibroblast cell line (QT6) [8].
• Functional analysis of the GFP-GLYT1 and GFP-GLYT2 stable cell lines demonstrated that they exhibited high affinity for glycine and the characteristic properties of both glycine transporter subtypes [9].
• The subcellular localization of glycine transporters one (GLYT1) and two (GLYT2) stably expressed in PC12 cells has been studied [9].

Associations of SLC6A9 with chemical compounds

• A chimeric GLYT2 (GLYT2a-EL1) that contains GLYT1 sequences in this region, including the relevant cysteine, was sensitive to the reagent, and its sensitivity was decreased by co-substrates [10].
• GLYT1 is selectively inhibited by the sarcosine derivative N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-propyl]sarcosine (NFPS) [11].
• GLYT1, expressed in glial processes of glycinergic areas and in glia and neurons of glutamatergic pathways that contain N-methyl-d-aspartate (NMDA) receptors, is essential for regulating glycine levels both at glycinergic and NMDA-containing synapses [11].
• Differential effects of ethanol on glycine uptake mediated by the recombinant GLYT1 and GLYT2 glycine transporters [12].
• The synaptic action of glycine is terminated by two sodium- and chloride-coupled transporters, GLYT1 and GLYT2, located in the glial plasma membrane and in the presynaptic terminals, respectively [13].

Other interactions of SLC6A9

• Two forms of glycine transporter have been described to date, GlyT-1 and GlyT-2 [14].
• It is expected that non-transportable, non-competitive inhibitors of GlyT1 may have therapeutic value in CNS disorders characterized by hypofunctional NMDA receptor-mediated glutamatergic neurotransmission [15].
• Blockade of selective GLT-1 (EAAT2) and GlyT1, as well as nonspecific transporters, did not inhibit or had no effect on uptake of aluminum in complex with the corresponding amino acids [16].

References