Psychiatry related information on SLC6A5

• No association between genetic variants at the GLYT2 gene and bipolar affective disorder and schizophrenia [1].

High impact information on SLC6A5

• Here we show that missense, nonsense and frameshift mutations in SLC6A5 (ref. 8), encoding the presynaptic glycine transporter 2 (GlyT2), also cause hyperekplexia [2].
• SLC6A5 mutations result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na+ binding sites [2].
• Most interestingly, the plasma membrane insertion of the WT-hNET and hNET double mutant were not affected by beta-PMA [3].
• In addition, the PKC-induced phosphorylation of hNET double mutant was significantly reduced [3].
• In the absence of T258A and S259A mutations, alanine substitution of all other potential phosphosites within the hNET did not block PKC-induced phosphorylation and down-regulation [3].

Biological context of SLC6A5

• Radiation hybrid analysis mapped the GlyT2 gene to D11S1308 (LOD=8.988) on human chromosome 11p15.1-15.2 [4].
• Molecular cloning and functional expression of the human glycine transporter GlyT2 and chromosomal localisation of the gene in the human genome [4].
• The isolated sequence exhibits 89% homology with the previously isolated rat GlyT2 cDNA (Liu et al., J. Biol. Chem. 268 (1993) 22802-22808) at the nucleotide level, and 93% amino acid sequence identity [5].
• The human glycine transporter type 2 (hGlyT2) was cloned from a spinal cord cDNA library using PCR-based methodologies [5].
• When expressed in polarized MDCK cells, wild type GLYT2 localizes in the apical surface as assessed by transport and biotinylation assays [6].

Anatomical context of SLC6A5

• The GlyT-2 form is expressed mainly in the spinal cord, brainstem and cerebellum [7].
• When stably expressed in CHO cells, human GlyT2 displays a dose-dependent uptake of glycine with an apparent Km of 108 microM [4].
• Expression of the intact hGlyT2 transporter sequence in COS-7 cells resulted in a 10-fold increase in high-affinity uptake relative to control cells transfected with vector alone [5].
• The role of N-glycosylation in transport to the plasma membrane and sorting of the neuronal glycine transporter GLYT2 [6].
• 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 [8].

Associations of SLC6A5 with chemical compounds

• We have cloned and sequenced a cDNA encoding the human type 2 glycine transporter GlyT2 from human brain and spinal cord [4].
• Like rat GlyT2, the high-affinity uptake mediated by hGlyT2 was found to be insensitive to the GlyT1 inhibitor sarcosine [5].
• 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 [9].
• Glycine transporter GLYT2 is an axonal glycoprotein involved in the removal of glycine from the synaptic cleft [6].
• GLYT2 lacks a conserved cysteine in the first hydrophilic loop (EL1) that is reactive to [2-(trimethylammonium)ethyl] methanethiosulfonate (MTSET) in related transporters [9].

Other interactions of SLC6A5

• Two forms of glycine transporter have been described to date, GlyT-1 and GlyT-2 [7].

Analytical, diagnostic and therapeutic context of SLC6A5

• Site-directed mutagenesis of the four glycosylation sites (Asn-345, Asn-355, Asn-360, and Asn-366), located in the large extracellular loop of GLYT2, produced an inactive protein that was retained in intracellular compartments when transiently transfected in COS cells or in nonpolarized MDCK cells [6].
• Our findings further showed that the non-radioactive in situ hybridization technique for identifying GlyT2 mRNA in fixed free-floating sections is a highly efficient tool for identifying glycinergic neurons in the spinal cord [10].
• Western analysis and immunocytochemistry in frozen sections of mouse brain demonstrated a clear caudal-rostral gradient of GLYT2 distribution, with massive accumulation in the spinal cord and brainstem and less in the cerebellum [11].

References