glycine plasma membrane transport proteins

Summary

Summary: A family of sodium chloride-dependent neurotransmitter symporters that transport the amino acid GLYCINE. They differ from GLYCINE RECEPTORS, which signal cellular responses to GLYCINE. They are located primarily on the PLASMA MEMBRANE of NEURONS; GLIAL CELLS; EPITHELIAL CELLS; and RED BLOOD CELLS where they remove inhibitory neurotransmitter glycine from the EXTRACELLULAR SPACE.

Top Publications

  1. REED B, Sullivan S, Tsai G, Coyle J, Esguerra M, Miller R. The glycine transporter GlyT1 controls N-methyl-D-aspartic acid receptor coagonist occupancy in the mouse retina. Eur J Neurosci. 2009;30:2308-17 pubmed publisher
    ..These observations are discussed in view of contemporary issues about NMDA receptor coagonist function in the vertebrate retina and the role of glycine vs. D-serine as the endogenous coagonist. ..
  2. Carta E, Chung S, James V, Robinson A, Gill J, Remy N, et al. Mutations in the GlyT2 gene (SLC6A5) are a second major cause of startle disease. J Biol Chem. 2012;287:28975-85 pubmed publisher
    ..This study firmly establishes the combination of missense, nonsense, frameshift, and splice site mutations in the GlyT2 gene as the second major cause of startle disease. ..
  3. Pedroarena C, Kamphausen S. Glycinergic synaptic currents in the deep cerebellar nuclei. Neuropharmacology. 2008;54:784-95 pubmed publisher
    ..The present study, by demonstrating fast glycinergic IPSCs in mature DCNs, points to the activation of glycinergic microcircuits as one of the possible mechanism involved in the spatio-temporal control of cerebellar output. ..
  4. Lindsley C, Shipe W, Wolkenberg S, Theberge C, Williams D, Sur C, et al. Progress towards validating the NMDA receptor hypofunction hypothesis of schizophrenia. Curr Top Med Chem. 2006;6:771-85 pubmed
    ..Other potential targets for modulating NMDA receptor currents (polyamine sites, muscarinic receptors, etc...) will also be addressed briefly. ..
  5. Depoortere R, Dargazanli G, Estenne Bouhtou G, Coste A, Lanneau C, Desvignes C, et al. Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic. Neuropsychopharmacology. 2005;30:1963-85 pubmed
    ..By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states. ..
  6. Eulenburg V, Armsen W, Betz H, Gomeza J. Glycine transporters: essential regulators of neurotransmission. Trends Biochem Sci. 2005;30:325-33 pubmed
    ..Selective GlyT inhibitors could be of therapeutic value in cognitive disorders, schizophrenia and pain. ..
  7. Fornés A, Núñez E, Aragón C, López Corcuera B. The second intracellular loop of the glycine transporter 2 contains crucial residues for glycine transport and phorbol ester-induced regulation. J Biol Chem. 2004;279:22934-43 pubmed
    ..Our results establish a new structural basis for the action of PMA on GLYT2 and suggest a complex nature of the PMA action on this glycine transporter. ..
  8. Gomeza J, Hülsmann S, Ohno K, Eulenburg V, Szoke K, Richter D, et al. Inactivation of the glycine transporter 1 gene discloses vital role of glial glycine uptake in glycinergic inhibition. Neuron. 2003;40:785-96 pubmed
    ..Thus, during early postnatal life, GlyT1 is essential for regulating glycine concentrations at inhibitory GlyRs, and GlyT1 deletion generates symptoms found in human glycine encephalopathy. ..
  9. Lowe J, Drozda S, Fisher K, Strick C, Lebel L, Schmidt C, et al. [3H]-(R)-NPTS, a radioligand for the type 1 glycine transporter. Bioorg Med Chem Lett. 2003;13:1291-2 pubmed
    ..The synthesis of NPTS, 6, a potent inhibitor of the type 1 glycine transporter (GlyT1) is described, as well as preparation of 6 in optically active and tritiated form for use as a radioligand for affinity displacement assay of GlyT1. ..

More Information

Publications62

  1. Pérez Siles G, Núñez E, Morreale A, Jiménez E, Leo Macias A, Pita G, et al. An aspartate residue in the external vestibule of GLYT2 (glycine transporter 2) controls cation access and transport coupling. Biochem J. 2012;442:323-34 pubmed publisher
    ..On the basis of these findings, we propose a role for Asp471 in controlling cation access to GLYT2 Na+ sites, ion coupling during transport and the subsequent conformational changes. ..
  2. Rees M, Harvey K, Pearce B, Chung S, Duguid I, Thomas P, et al. Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Nat Genet. 2006;38:801-6 pubmed
    ..SLC6A5 mutations result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na+ binding sites. ..
  3. Kim K, Kingsmore S, Han H, Yang Feng T, Godinot N, Seldin M, et al. Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes. Mol Pharmacol. 1994;45:608-17 pubmed
    ..These variants point to regions of the glycine transporter that might be important in the processing or transport function of this protein. ..
  4. Jamra R, Villela A, Klein K, Becker T, Schulze T, Schmael C, et al. No association between genetic variants at the GLYT2 gene and bipolar affective disorder and schizophrenia. Psychiatr Genet. 2006;16:91 pubmed
  5. Hashimoto K, Fujita Y, Ishima T, Chaki S, Iyo M. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the glycine transporter-1 inhibitor NFPS and D-serine. Eur Neuropsychopharmacol. 2008;18:414-21 pubmed
  6. Li S, Mo Z, Yang X, Price S, Shen M, Xiang M. Foxn4 controls the genesis of amacrine and horizontal cells by retinal progenitors. Neuron. 2004;43:795-807 pubmed
    ..Our data suggest a model in which Foxn4 cooperates with other key retinogenic factors to mediate the multipotent differentiation of retinal progenitors. ..
  7. Geerlings A, Núñez E, Rodenstein L, López Corcuera B, Aragón C. Glycine transporter isoforms show differential subcellular localization in PC12 cells. J Neurochem. 2002;82:58-65 pubmed
    ..GFP-GLYT1 was mainly localized on the plasma membrane, whereas most of GFP-GLYT2 was present on large dense-core vesicles and endosomes. Both transporters were absent from the synaptic vesicle population in PC12 cells. ..
  8. Gomeza J, Ohno K, Hülsmann S, Armsen W, Eulenburg V, Richter D, et al. Deletion of the mouse glycine transporter 2 results in a hyperekplexia phenotype and postnatal lethality. Neuron. 2003;40:797-806 pubmed
    ..Thus, postnatal GlyT2 function is crucial for efficient transmitter loading of synaptic vesicles in glycinergic nerve terminals, and the GlyT2 gene constitutes a candidate disease gene in human hyperekplexia patients. ..
  9. Haranishi Y, Hara K, Terada T, Nakamura S, Sata T. The antinociceptive effect of intrathecal administration of glycine transporter-2 inhibitor ALX1393 in a rat acute pain model. Anesth Analg. 2010;110:615-21 pubmed publisher
    ..These findings suggest that the inhibitory neurotransmitter transporters are promising targets for the treatment of acute pain and that the selective inhibitor of GlyT2 could be a novel therapeutic drug. ..
  10. Rousseau F, Aubrey K, Supplisson S. The glycine transporter GlyT2 controls the dynamics of synaptic vesicle refilling in inhibitory spinal cord neurons. J Neurosci. 2008;28:9755-68 pubmed publisher
    ..Thus, our results demonstrate the central role played by GlyT2 in determining inhibitory phenotype and therefore in the physiology and pathology of inhibitory circuits. ..
  11. Tanaka I, Ezure K. Overall distribution of GLYT2 mRNA-containing versus GAD67 mRNA-containing neurons and colocalization of both mRNAs in midbrain, pons, and cerebellum in rats. Neurosci Res. 2004;49:165-78 pubmed
    ..The present study suggests that the corelease of glycine and GABA from single neurons is more widespread than has been reported. ..
  12. Jiménez E, Zafra F, Pérez Sen R, Delicado E, Miras Portugal M, Aragón C, et al. P2Y purinergic regulation of the glycine neurotransmitter transporters. J Biol Chem. 2011;286:10712-24 pubmed publisher
    ..Our data may help define the role of GLYTs in nociception and pain sensitization. ..
  13. Yee B, Balic E, Singer P, Schwerdel C, Grampp T, Gabernet L, et al. Disruption of glycine transporter 1 restricted to forebrain neurons is associated with a procognitive and antipsychotic phenotypic profile. J Neurosci. 2006;26:3169-81 pubmed
  14. Tsai S, Cheng C, Hong C, Liao D, Hou S, Yen F, et al. Association study of polymorphisms in glycine transporter with schizophrenia. J Neural Transm (Vienna). 2006;113:1545-9 pubmed
    ..Further studies with other GlyT1 variants, relating either to schizophrenia, psychotic symptoms or to therapeutic response in schizophrenia, are suggested. ..
  15. Charlier C, Coppieters W, Rollin F, Desmecht D, Agerholm J, Cambisano N, et al. Highly effective SNP-based association mapping and management of recessive defects in livestock. Nat Genet. 2008;40:449-54 pubmed publisher
    ..Identification of these causative mutations has an immediate translation into breeding practice, allowing marker assisted selection against the defects through avoidance of at-risk matings...
  16. Beato M. The time course of transmitter at glycinergic synapses onto motoneurons. J Neurosci. 2008;28:7412-25 pubmed publisher
    ..2-3.5 mM and is cleared from the cleft with a time constant of 0.6-0.9 ms. ..
  17. Mezler M, Hornberger W, Mueller R, Schmidt M, Amberg W, Amberg M, et al. Inhibitors of GlyT1 affect glycine transport via discrete binding sites. Mol Pharmacol. 2008;74:1705-15 pubmed publisher
    ..The divergent modes of inhibition may significantly affect the efficacy and tolerability of these drugs. ..
  18. Hashimoto K. Glycine transporter inhibitors as therapeutic agents for schizophrenia. Recent Pat CNS Drug Discov. 2006;1:43-53 pubmed
    ..In this article, the author reviews the recent important patents on GlyT-1 inhibitors for treatment of schizophrenia and other psychiatric diseases associated with the NMDA receptor hypofunction. ..
  19. Núñez E, Pérez Siles G, Rodenstein L, Alonso Torres P, Zafra F, Jiménez E, et al. Subcellular localization of the neuronal glycine transporter GLYT2 in brainstem. Traffic. 2009;10:829-43 pubmed publisher
    ..Therefore, the intracellular GLYT2 resides in a subset of endosomal membranes and may traffic around several compartments, mainly Rab11-positive endosomes. ..
  20. Eulenburg V, Becker K, Gomeza J, Schmitt B, Becker C, Betz H. Mutations within the human GLYT2 (SLC6A5) gene associated with hyperekplexia. Biochem Biophys Res Commun. 2006;348:400-5 pubmed
    ..One of the GLYT2 mutations identified causes truncation of the transporter protein and a complete loss of transport function. Our results are consistent with GLYT2 being a disease gene in human hyperekplexia. ..
  21. Zhang H, Hyrc K, Thio L. The glycine transport inhibitor sarcosine is an NMDA receptor co-agonist that differs from glycine. J Physiol. 2009;587:3207-20 pubmed publisher
    ..The same was true for neuronal bursting. Thus, sarcosine may enhance NMDAR function by more than one mechanism and may have different effects from other NMDAR co-agonists. ..
  22. Yang S, Hong C, Huang Y, Tsai S. The effects of glycine transporter I inhibitor, N-methylglycine (sarcosine), on ketamine-induced alterations in sensorimotor gating and regional brain c-Fos expression in rats. Neurosci Lett. 2010;469:127-30 pubmed publisher
    ..However, in the olfactory bulb, sarcosine, but not clozapine, significantly reduced the ketamine-induced increase in c-Fos expression. Our animal study demonstrated that sarcosine may have antipsychotic potential. ..
  23. Whitehead K, Pearce S, Walker G, Sundaram H, Hill D, Bowery N. Positive N-methyl-D-aspartate receptor modulation by selective glycine transporter-1 inhibition in the rat dorsal spinal cord in vivo. Neuroscience. 2004;126:381-90 pubmed
    ..Such a mechanism could be important to NMDA-R-mediated synaptic plasticity in the spinal cord and be of relevance to the clinical usage of GlyT-1 inhibitors. ..
  24. Manahan Vaughan D, Wildförster V, Thomsen C. Rescue of hippocampal LTP and learning deficits in a rat model of psychosis by inhibition of glycine transporter-1 (GlyT1). Eur J Neurosci. 2008;28:1342-50 pubmed publisher
    ..Use of the inhibitor in healthy subjects is neither beneficial to synaptic plasticity nor hippocampus-dependent learning. ..
  25. de Juan Sanz J, Zafra F, López Corcuera B, Aragón C. Endocytosis of the neuronal glycine transporter GLYT2: role of membrane rafts and protein kinase C-dependent ubiquitination. Traffic. 2011;12:1850-67 pubmed publisher
    ..These findings may reveal new therapeutic targets to address glycinergic pathologies associated with alterations in GLYT2 trafficking. ..
  26. Uusisaari M, Knopfel T. GlyT2+ neurons in the lateral cerebellar nucleus. Cerebellum. 2010;9:42-55 pubmed publisher
    ..Presence of this so far undescribed DCN neuron population in the lateral nucleus suggests a direct inhibitory pathway from the DCN to the cerebellar cortex. ..
  27. Gill J, Capper D, Vanbellinghen J, Chung S, Higgins R, Rees M, et al. Startle disease in Irish wolfhounds associated with a microdeletion in the glycine transporter GlyT2 gene. Neurobiol Dis. 2011;43:184-9 pubmed publisher
    ..These findings will inform future breeding strategies and enable a rational pharmacotherapy of this new canine disorder. ..
  28. Jursky F, Nelson N. Localization of glycine neurotransmitter transporter (GLYT2) reveals correlation with the distribution of glycine receptor. J Neurochem. 1995;64:1026-33 pubmed
    ..The results indicate that GLYT2 is involved in the termination of glycine neurotransmission accompanying the glycine receptor at the classic inhibitory system in the hindbrain. ..
  29. Javitt D. Glycine transport inhibitors and the treatment of schizophrenia. Biol Psychiatry. 2008;63:6-8 pubmed
  30. Armsen W, Himmel B, Betz H, Eulenburg V. The C-terminal PDZ-ligand motif of the neuronal glycine transporter GlyT2 is required for efficient synaptic localization. Mol Cell Neurosci. 2007;36:369-80 pubmed
    ..These data indicate that the C-terminal PDZ-ligand motif of GlyT2 plays an important role in transporter trafficking to and/or stabilization at synaptic sites. ..
  31. Cubelos B, Giménez C, Zafra F. Localization of the GLYT1 glycine transporter at glutamatergic synapses in the rat brain. Cereb Cortex. 2005;15:448-59 pubmed
    ..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. ..
  32. Lechner S. Glutamate-based therapeutic approaches: inhibitors of glycine transport. Curr Opin Pharmacol. 2006;6:75-81 pubmed
  33. Giménez C, Pérez Siles G, Martínez Villarreal J, Arribas González E, Jiménez E, Núñez E, et al. A novel dominant hyperekplexia mutation Y705C alters trafficking and biochemical properties of the presynaptic glycine transporter GlyT2. J Biol Chem. 2012;287:28986-9002 pubmed publisher
    ..Additionally, Y705C presents altered H(+) and Zn(2+) dependence of glycine transport that may affect the function of glycinergic neurotransmission in vivo. ..
  34. Núñez E, Alonso Torres P, Fornés A, Aragón C, López Corcuera B. The neuronal glycine transporter GLYT2 associates with membrane rafts: functional modulation by lipid environment. J Neurochem. 2008;105:2080-90 pubmed publisher
    ..Thus, GLYT2 may require membrane raft location for optimal function, and therefore the lipid environment may constitute a new mechanism to modulate GLYT2. ..
  35. Smith K, Borden L, Hartig P, Branchek T, Weinshank R. Cloning and expression of a glycine transporter reveal colocalization with NMDA receptors. Neuron. 1992;8:927-35 pubmed
    ..The identification of this transporter therefore opens the study of the molecular mechanisms underlying both inhibitory glycinergic transmission and NMDA-mediated excitatory transmission. ..
  36. Legendre P. The glycinergic inhibitory synapse. Cell Mol Life Sci. 2001;58:760-93 pubmed
    ..Clearly, recent work on glycine receptor channels and the synapses at which they mediate inhibitory signalling in both young and adult animals necessitates an update of our vision of glycinergic inhibitory transmission. ..
  37. Hossaini M, Duraku L, Saraç C, Jongen J, Holstege J. Differential distribution of activated spinal neurons containing glycine and/or GABA and expressing c-fos in acute and chronic pain models. Pain. 2010;151:356-65 pubmed publisher
    ..This mechanism, together with mechanisms that antagonize the effects of GABA and glycine at the receptor level, may determine the sensitivity of our pain system during health and disease. ..
  38. Zeilhofer H, Studler B, Arabadzisz D, Schweizer C, Ahmadi S, Layh B, et al. Glycinergic neurons expressing enhanced green fluorescent protein in bacterial artificial chromosome transgenic mice. J Comp Neurol. 2005;482:123-41 pubmed
  39. Fernández Sánchez E, Martínez Villarreal J, Giménez C, Zafra F. Constitutive and regulated endocytosis of the glycine transporter GLYT1b is controlled by ubiquitination. J Biol Chem. 2009;284:19482-92 pubmed publisher
    ..It remains to be determined whether GLYT1b recycling might be affected in pathologies involving alterations to the ubiquitin system, thereby interfering with its influence on inhibitory and excitatory neurotransmission. ..
  40. Betz H, Gomeza J, Armsen W, Scholze P, Eulenburg V. Glycine transporters: essential regulators of synaptic transmission. Biochem Soc Trans. 2006;34:55-8 pubmed
    ..We have identified different interacting proteins that may play a role in GlyT2 trafficking and/or pre-synaptic localization. ..
  41. Lindsley C, Wolkenberg S, Kinney G. Progress in the preparation and testing of glycine transporter type-1 (GlyT1) inhibitors. Curr Top Med Chem. 2006;6:1883-96 pubmed
  42. Tsai G, Ralph Williams R, Martina M, Bergeron R, Berger Sweeney J, Dunham K, et al. Gene knockout of glycine transporter 1: characterization of the behavioral phenotype. Proc Natl Acad Sci U S A. 2004;101:8485-90 pubmed
  43. Aragón C, López Corcuera B. Structure, function and regulation of glycine neurotransporters. Eur J Pharmacol. 2003;479:249-62 pubmed
    ..This review deals on recent progress on localization, transport mechanisms, structure, regulation and pharmacology of the glycine transporters (GLYTs). ..
  44. Atkinson B, Bell S, De Vivo M, Kowalski L, Lechner S, Ognyanov V, et al. ALX 5407: a potent, selective inhibitor of the hGlyT1 glycine transporter. Mol Pharmacol. 2001;60:1414-20 pubmed
    ..ALX 5407 represents a novel tool in the investigation of N-methyl-D-aspartate-receptor function. This class of drug may lead to novel therapies in the treatment of schizophrenia. ..
  45. Deng X, Sagata N, Takeuchi N, Tanaka M, Ninomiya H, Iwata N, et al. Association study of polymorphisms in the neutral amino acid transporter genes SLC1A4, SLC1A5 and the glycine transporter genes SLC6A5, SLC6A9 with schizophrenia. BMC Psychiatry. 2008;8:58 pubmed publisher
    ..We report here association studies of schizophrenia with SLC1A4, SLC1A5 encoding neutral amino acid transporters ASCT1, ASCT2, and SLC6A5, SLC6A9 encoding glycine transporters GLYT2, GLYT1, respectively...
  46. Aragón C, López Corcuera B. Glycine transporters: crucial roles of pharmacological interest revealed by gene deletion. Trends Pharmacol Sci. 2005;26:283-6 pubmed
    ..In addition, molecular and behavioural analysis of heterozygous mice has confirmed the therapeutic potential of GLYT1 inhibitors in the treatment of several neurological and psychiatric disorders. ..
  47. Herdon H, Roberts J, Coulton S, Porter R. Pharmacological characterisation of the GlyT-1 glycine transporter using two novel radioligands. Neuropharmacology. 2010;59:558-65 pubmed publisher
  48. Simat M, Ambrosetti L, Lardi Studler B, Fritschy J. GABAergic synaptogenesis marks the onset of differentiation of basket and stellate cells in mouse cerebellum. Eur J Neurosci. 2007;26:2239-56 pubmed
  49. Zeng Z, O Brien J, Lemaire W, O Malley S, Miller P, Zhao Z, et al. A novel radioligand for glycine transporter 1: characterization and use in autoradiographic and in vivo brain occupancy studies. Nucl Med Biol. 2008;35:315-25 pubmed publisher
  50. Karasawa J, Hashimoto K, Chaki S. D-Serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats. Behav Brain Res. 2008;186:78-83 pubmed
    ..The results also suggest that enhancing NMDA receptor function is an effective way for treating the cognitive deficits associated with schizophrenia. ..
  51. Borowsky B, Mezey E, Hoffman B. Two glycine transporter variants with distinct localization in the CNS and peripheral tissues are encoded by a common gene. Neuron. 1993;10:851-63 pubmed
    ..The anatomic distribution of GLYT-2 mRNA supports the emerging status of glycine as a supraspinal neurotransmitter and suggests that glycine may function as a chemical messenger outside the CNS. ..
  52. Black M, Varty G, Arad M, Barak S, De Levie A, Boulay D, et al. Procognitive and antipsychotic efficacy of glycine transport 1 inhibitors (GlyT1) in acute and neurodevelopmental models of schizophrenia: latent inhibition studies in the rat. Psychopharmacology (Berl). 2009;202:385-96 pubmed publisher
    ..These preclinical data, from acute and neurodevelopmental models, suggest that GlyT1 inhibition may exhibit activity in the positive, negative, and cognitive symptom domains of schizophrenia. ..
  53. Sugane T, Tobe T, Hamaguchi W, Shimada I, Maeno K, Miyata J, et al. Synthesis and biological evaluation of (4H-1,2,4-triazol-4-yl)isoquinoline derivatives as selective glycine transporter 1 inhibitors. Bioorg Med Chem. 2012;20:34-41 pubmed publisher
    ..15 also showed improved aqueous solubility and in vivo efficacy on (+)-HA966-induced hyperlocomotion in mice over the lead compound. ..