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Slc6a9  -  solute carrier family 6 (neurotransmitter...

Rattus norvegicus

Synonyms: GLYT-1, GLYT-1b, GlyT-1, GlyT1, Glyt1, ...
 
 
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Disease relevance of Slc6a9

  • In retina, which expresses only GlyT1 but not GlyT2, Ulip6 was detected in the inner plexiform layer and along the somata and processes of selected bipolar, amacrine and ganglion cells [1].
  • Since cerebral glycine concentration in the vicinity of NMDA receptors is thought to be controlled by the glia expressed glycine transporter type 1 (GlyT1), the effects of several typical and atypical antipsychotics on glycine uptake were examined in human placenta choriocarcinoma (JAR) cells expressing human GlyT1a [2].
  • Reduced expression of astrocytic glycine transporter (Glyt-1) in acute liver failure [3].
  • As astrocytic transporters regulate the amino acid concentrations within excitatory synapses, the expression of Glyt-1 was studied in cortical preparations from rats with ischemic liver failure induced by portacaval anastomosis followed 24 hr later by hepatic artery ligation and from appropriate sham-operated controls [3].
  • The GLYT1 mRNA was transiently upregulated by the second day after ischemia in astrocytelike cells in close vicinity to hippocampal CA1 pyramidal neurons, possibly to reduce glycine concentration in the local extracellular spaces [4].
 

Psychiatry related information on Slc6a9

 

High impact information on Slc6a9

  • We have isolated a cDNA encoding a high affinity, Na+/Cl(-)-dependent glycine transporter, GLYT-2, which is distinct from another glycine transporter, GLYT-1 [6].
  • GLYT-1 is found only in the white matter of the CNS, while GLYT-2 is found in the gray matter of the CNS as well as in macrophages and mast cells in peripheral tissues [6].
  • Data obtained from whole-cell patch-clamp recordings of hippocampal pyramidal neurons, in vitro, demonstrated that exogenous glycine and glycine transporter type 1 (GLYT1) antagonist selectively enhanced the amplitude of the NMDA component of a glutamatergic excitatory postsynaptic current [7].
  • In situ hybridization reveals that GLYT1 is prominently expressed in the cervical spinal cord and brainstem, two regions of the central nervous system where glycine is a putative neurotransmitter [8].
  • [3H]Glycine transport mediated by clone GLYT1 is blocked by sarcosine but is not blocked by methyl-aminoisobutyric acid or L-alanine, a substrate specificity similar to that described for a previously identified glycine-uptake system called system Gly [8].
 

Biological context of Slc6a9

  • The open reading frame of the GLYT1 cDNA predicts a protein containing 633 amino acids with a molecular mass of approximately 70 kDA [8].
  • By combining RNase protection and rapid amplification of cDNA ends analysis, we have determined transcription start sites for GLYT-1a and GLYT-1b [9].
  • The GLYT-1 gene contains three sets of dinucleotide repeats, two AC repeats, and one TG repeat which may form stem-loop structures to either facilitate or interfere with transcription of one of the transporter isoforms [9].
  • The GLYT-1 gene contains 15 exons, with the first two specific for GLYT-1a and the third specific for GLYT-1b [9].
  • The rat GLYT-1 gene encodes two glycine transporter variants, GLYT-1a and GLYT-1b, that differ in NH2 termini and 5'-noncoding regions as well as in tissue distribution [9].
 

Anatomical context of Slc6a9

  • A cDNA clone encoding a glycine transporter has been isolated from rat brain by a combined PCR and plaque-hybridization strategy. mRNA synthesized from this clone (designated GLYT1) directs the expression of sodium- and chloride-dependent, high-affinity uptake of [3H]glycine by Xenopus oocytes [8].
  • Despite the presence of GLYT1 mRNA in both glial cells and in glutamatergic neurons, previous studies have mainly localized GLYT1 immunoreactivity to glial cells in the caudal regions of the nervous system [10].
  • In conclusion, the close spatial association of GLYT1 and glutamatergic synapses strongly supports a role for this protein in neurotransmission mediated by NMDA receptors in the forebrain, and perhaps in other regions of the CNS [10].
  • Using whole cell voltage clamp recordings from lamina X neurones in rat spinal cord slices, we investigated the effect of glycine transporter (GlyT) antagonists on both glycinergic inhibitory postsynaptic current (IPSCs) and glutamatergic excitatory postsynaptic current (EPSCs) [11].
  • Co-transfection of syntaxin 1A with GLYT1 or GLYT2 in COS cells resulted in approximately 40% inhibition in glycine transport [12].
 

Associations of Slc6a9 with chemical compounds

  • Org 25935 is an inhibitor of the glycine transporter 1 (GlyT1) protein with negligible action on the glycine transporter 2 (GlyT2) protein [13].
  • The primary structure and hydropathicity profile of GLYT1 protein reveal that this protein is a member of the sodium- and chloride-dependent superfamily of transporters that utilize neurotransmitters and related substances as substrates [8].
  • These data provide evidence that the observed increased in extracellular citrulline is a consequence of positive modulation of NMDA-R, secondary to increased extracellular glycine and support a protective role for GlyT-1 against fluctuations in extracellular glycine uptake at glutamatergic synapses in the dorsal spinal cord [14].
  • They differ only at their amino-terminal sequences, and GLYT1b contains two additional potential phosphorylation sites for proline-dependent kinase [15].
  • The GLYT1 subtypes of glycine transporter are expressed in glia surrounding excitatory synapses in the mammalian CNS and may regulate synaptic glycine concentrations required for activation of the NMDA subtypes of glutamate receptor [16].
  • In the context of the full-length transporter, lysine 619 played a prominent role in both the constitutive and phorbol 12-myristate 13-acetate-induced endocytosis of GLYT1b, suggesting the involvement of ubiquitin modification of GLYT1b during the internalization process [17].
 

Regulatory relationships of Slc6a9

 

Other interactions of Slc6a9

  • In addition, we demonstrated that GLYT1 was physically associated with the NMDA receptor in a biochemical assay [10].
  • Unc-33-like protein (Ulip)6, a brain-specific phosphoprotein of the Ulip/collapsin response mediator protein family, was originally identified in our laboratory by yeast two-hybrid screening using the cytoplasmic N-terminal domain of the neuronal glycine transporter, glycine transporter (GlyT) 2, as a bait [1].
  • Immunoblots show that the 50-70 kDa band corresponding to GLYT1 is expressed at the highest concentrations in the spinal cord, brainstem, diencephalon, and retina, and, in a lesser degree, to the olfactory bulb and brain hemispheres, whereas it is not detected in peripheral tissues [18].
 

Analytical, diagnostic and therapeutic context of Slc6a9

  • Moreover, through electron microscopy, we observed an enrichment of GLYT1 in both the presynaptic and the postsynaptic aspects of putative glutamatergic terminals that established asymmetric synapses [10].
  • Double labeling confocal microscopy with the glutamatergic marker vGLUT1 revealed an enrichment of GLYT1 in a subpopulation of glutamatergic terminals [10].
  • By means of immunocytochemistry, we analyzed the amino acid glycine (Gly), the glycine transporters 1 and 2 (GlyT1, GlyT2), and the ligand binding glycine receptor-subunit alpha 1 (GlyR alpha 1) [19].
  • Expression of Glyt-1 mRNA, studied by reverse transcriptase-polymerase chain reaction, was significantly decreased in the brain at coma stages of encephalopathy (to approximately 50% of control) concomitant with a significant threefold increase of extracellular glycine, measured by in vivo cerebral microdialysis [3].
  • By using site-directed mutagenesis we have been able to identify signals for basolateral/somatodendritic localization in the amino-terminal region of GLYT1 and in two dileucine motifs located in the carboxyl tail of this protein [20].

References

  1. Cellular localization and subcellular distribution of Unc-33-like protein 6, a brain-specific protein of the collapsin response mediator protein family that interacts with the neuronal glycine transporter 2. Horiuchi, M., Loebrich, S., Brandstaetter, J.H., Kneussel, M., Betz, H. J. Neurochem. (2005) [Pubmed]
  2. Effects of typical and atypical antipsychotics on human glycine transporters. Williams, J.B., Mallorga, P.J., Jeffrey Conn, P., Pettibone, D.J., Sur, C. Schizophr. Res. (2004) [Pubmed]
  3. Reduced expression of astrocytic glycine transporter (Glyt-1) in acute liver failure. Zwingmann, C., Desjardins, P., Hazell, A., Chatauret, N., Michalak, A., Butterworth, R.F. Metabolic brain disease. (2002) [Pubmed]
  4. Differential expressions of glycine transporter 1 and three glutamate transporter mRNA in the hippocampus of gerbils with transient forebrain ischemia. Fujita, H., Sato, K., Wen, T.C., Peng, Y., Sakanaka, M. J. Cereb. Blood Flow Metab. (1999) [Pubmed]
  5. Differential properties of two stably expressed brain-specific glycine transporters. López-Corcuera, B., Martínez-Maza, R., Núñez, E., Roux, M., Supplisson, S., Aragón, C. J. Neurochem. (1998) [Pubmed]
  6. Two glycine transporter variants with distinct localization in the CNS and peripheral tissues are encoded by a common gene. Borowsky, B., Mezey, E., Hoffman, B.J. Neuron (1993) [Pubmed]
  7. Modulation of N-methyl-D-aspartate receptor function by glycine transport. Bergeron, R., Meyer, T.M., Coyle, J.T., Greene, R.W. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  8. Cloning, expression, and localization of a rat brain high-affinity glycine transporter. Guastella, J., Brecha, N., Weigmann, C., Lester, H.A., Davidson, N. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  9. Analysis of a gene encoding two glycine transporter variants reveals alternative promoter usage and a novel gene structure. Borowsky, B., Hoffman, B.J. J. Biol. Chem. (1998) [Pubmed]
  10. Localization of the GLYT1 glycine transporter at glutamatergic synapses in the rat brain. Cubelos, B., Giménez, C., Zafra, F. Cereb. Cortex (2005) [Pubmed]
  11. Role of glial and neuronal glycine transporters in the control of glycinergic and glutamatergic synaptic transmission in lamina X of the rat spinal cord. Bradaïa, A., Schlichter, R., Trouslard, J. J. Physiol. (Lond.) (2004) [Pubmed]
  12. Characterization of the interactions between the glycine transporters GLYT1 and GLYT2 and the SNARE protein syntaxin 1A. Geerlings, A., López-Corcuera, B., Aragón, C. FEBS Lett. (2000) [Pubmed]
  13. The glycine reuptake inhibitor org 25935 decreases ethanol intake and preference in male wistar rats. Molander, A., Lid??, H.H., L??f, E., Ericson, M., S??derpalm, B. Alcohol Alcohol. (2007) [Pubmed]
  14. Positive N-methyl-D-aspartate receptor modulation by selective glycine transporter-1 inhibition in the rat dorsal spinal cord in vivo. Whitehead, K.J., Pearce, S.M., Walker, G., Sundaram, H., Hill, D., Bowery, N.G. Neuroscience (2004) [Pubmed]
  15. Cloning and expression of a spinal cord- and brain-specific glycine transporter with novel structural features. Liu, Q.R., López-Corcuera, B., Mandiyan, S., Nelson, H., Nelson, N. J. Biol. Chem. (1993) [Pubmed]
  16. Arachidonic acid and anandamide have opposite modulatory actions at the glycine transporter, GLYT1a. Pearlman, R.J., Aubrey, K.R., Vandenberg, R.J. J. Neurochem. (2003) [Pubmed]
  17. Constitutive and regulated endocytosis of the glycine transporter GLYT1b is controlled by ubiquitination. Fernández-Sánchez, E., Martínez-Villarreal, J., Giménez, C., Zafra, F. J. Biol. Chem. (2009) [Pubmed]
  18. Glycine transporters are differentially expressed among CNS cells. Zafra, F., Aragón, C., Olivares, L., Danbolt, N.C., Giménez, C., Storm-Mathisen, J. J. Neurosci. (1995) [Pubmed]
  19. Glycine, glycine receptor subunit and glycine transporters in the rat parabrachial and Kölliker-Fuse nuclei. Herbert, H., Guthmann, A., Zafra, F., Ottersen, O.P. Anat. Embryol. (2000) [Pubmed]
  20. Polarized distribution of glycine transporter isoforms in epithelial and neuronal cells. Poyatos, I., Ruberti, F., Martínez-Maza, R., Giménez, C., Dotti, C.G., Zafra, F. Mol. Cell. Neurosci. (2000) [Pubmed]
 
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