High impact information on Slc6a9

• The analysis of GlyT knockout mice has revealed distinct functions of individual GlyT subtypes in synaptic transmission and provided animal models for two hereditary human diseases, glycine encephalopathy and hyperekplexia [1].
• Conversely, glycine or the GlyT1 inhibitor sarcosine suppress respiratory activity in slices from wild-type mice [2].
• Thus, reduced expression of GlyT1 enhances hippocampal NMDAR function and memory retention and protects against an amphetamine disruption of sensory gating, suggesting that drugs which inhibit GlyT1 might have both cognitive enhancing and antipsychotic effects [3].
• To characterize further the role of GlyT1, we generated mice in which the gene encoding GlyT1 was inactivated by homologous recombination through insertion of a PGK-Neo cassette in place of exons 2 and 3 [3].
• Both HMGN3a and HMGN3b upregulate the expression of the glycine transporter 1 gene (Glyt1) [4].

Biological context of Slc6a9

• We observed faster decay kinetics, reduced ifenprodil sensitivity and increased zinc-induced antagonism in N-methyl-d-aspartate receptor (NMDAR) currents of GlyT1+/- mice [5].
• To facilitate the morphological and functional analysis of glycinergic neurons, we generated bacterial artificial chromosome (BAC) transgenic mice, which specifically express enhanced green fluorescent protein (EGFP) under the control of the promotor of the glycine transporter (GlyT) 2 gene, which is a reliable marker for glycinergic neurons [6].
• Both GlyT1 and GlyT2 are essential for CNS function, as revealed by the lethal phenotypes of the respective knockout mice [7].

Anatomical context of Slc6a9

• In situ hybridization revealed GlyT1 expression in the developing spinal cord mainly in the ventral part of the ventricular zone at E12 [8].
• In the adult rat brain and spinal cord, GlyT1 hybridization signals were found exclusively in glial cells [8].
• Our genetic results indicate that at glycinergic synapses, the glial transporter GlyT1 catalyses the removal of glycine from the synaptic cleft, whereas GlyT2 is required for the re-uptake of glycine into nerve terminals, thereby allowing for neurotransmitter reloading of synaptic vesicles [7].
• Here, we achieved this by the generation of a novel mouse line (CamKIIalphaCre;Glyt1tm1.2fl/fl) with a neuron and forebrain selective disruption of glycine transporter 1 (GlyT1) [9].
• The vGluT3 amacrine cells expressed glycine and glycine transporter 1 (GlyT1) but not the vesicular glycine transporter (vesicular inhibitory amino acid transporter) [10].

Associations of Slc6a9 with chemical compounds

• Glyt1 encodes a membrane transporter that regulates the glycine concentration in synaptic junctions [4].
• The glial GlyT subtype GlyT1 is well located to activate NMDA receptors [11].
• The AMPA receptor potentiator LY451646, iGlu5 kainate receptor antagonist LY382884, glycine(B) receptor partial agonist D: -cycloserine, and GlyT-1 inhibitor ORG-24461 were ineffective in this model [12].

Other interactions of Slc6a9

• Two different glycine transporter genes, GlyT1 and GlyT2, have been described [8].

Analytical, diagnostic and therapeutic context of Slc6a9

• Chromatin immunoprecipitation assays showed that HMGN3 protein is recruited to a region of the Glyt1 gene encompassing the Glyt1a transcriptional start site [4].
• Real-time quantitative PCR revealed no transcripts in newborn homozygous [GlyT1(-/-)] mice and a 50% reduction in heterozygous (HZ) [GlyT1(+/-)] mice as compared with WT littermates [3].

References