Journal of Biomedical Science

, Volume 10, Issue 1, pp 30–36 | Cite as

Membrane glycine transport proteins

  • Godfrey Tunnicliff


Structurally, the simplest amino acid is glycine, and it has a number of important yet distinct functions in the body. This review focuses on the different transport systems and the associated carrier proteins for glycine that are responsible for its movement across biological membranes. Transport proteins in the class GLYT appear to be the most specific for glycine. However, the B0+ system also carries significant amounts of glycine. Other amino acid transport systems capable of carrying small amounts of glycine are ASC, asc and system L. In addition, an ATP-dependent transport process exists that takes up glycine into synaptic vesicles at nerve endings. This is known as the vesicular inhibitory amino acid transporter since, in addition to glycine, it can transport possibly two other inhibitory neurotransmitters.

Key Words

Glycine transport Transport proteins Neurotransmitters B0+ system Vesicular inhibitory amino acid transporter 


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  1. 1.
    Achterhof RA, Tunnicliff G. Kinetics of binding of [3H]glycine to transport proteins in channel catfish brain. Neurosignals 11:67–72;2002.Google Scholar
  2. 2.
    Adams RH, Sato K, Shimada S, Tohyama M, Püschel AW, Betz H. Gene structure and glial expression of the glycine transporter GLYT1 in embryonic and adult rodents. J Neurosci 15:2524–2532;1995.Google Scholar
  3. 3.
    Andersen V, Munck BG. Transport of the alpha-amino-mono-carboxylic acid L-alanine by the β-alanine carrier of the rabbit ileum. Biochim Biophys Acta 902:145–148;1987.Google Scholar
  4. 4.
    Angermeier SM, Shepard MD, Tunnicliff G. Glycine transport by red cells of channel catfish. Can J Zool 74:688–692;1996.Google Scholar
  5. 5.
    Aragón C, Giménez C. Efflux and exchange of glycine by synaptic plasma membrane vesicles derived from rat brain. Biochim Biophys Acta 855:257–264;1986.Google Scholar
  6. 6.
    Arriza JL, Kavanaugh MP, Fairman WA, Wu Y-N, Murdoch GH, North RA, Amara SG. Cloning and expression of a human neutral amino acid transporter with structural simlarity to the glutamate transporter gene family. J Biol Chem 268:15329–15332;1993.Google Scholar
  7. 7.
    Avery J, Jahn R, Edwardson JM. Reconstitution of regulated exocytosis in cell-free systems: A critical appraisal. Annu Rev Physiol 61:777–807;1999.Google Scholar
  8. 8.
    Baker DE, Knight PF. Calcium control of exocytosis and endocytosis in bovine adrenal medullary cells. Philos Trans R Soc Lond B Biol Sci 296:83–103;1981.Google Scholar
  9. 9.
    Bannai S, Tateishi N. Role of membrane transport in metabolism and function of glutathione in mammals. J Membr Biol 89:1–8;1986.Google Scholar
  10. 10.
    Bedet C, Isambert MF, Henry JP Gasnier B. Constitutive phosphorylation of the vesicular inhibitory amino acid transporter in rat central nervous system. J Neurochem 75:1654–1663;2000.Google Scholar
  11. 11.
    Belachew S, Malgrange B, Rigo JM, Rogister B, Leprince P, Hans G, Nguyen L, Moonen G. Glycine triggers an intracellular calcium influx in oligodendrocyte progenitor cells which is mediated by the activation of both the ionotropic glycine receptor and Na+-dependent transporters. Eur J Neurosci 12:1924–1930;2000.Google Scholar
  12. 12.
    Berger AJ, Dieudonne S, Ascher P. Glycine uptake governs glycine site occupancy at NMDA receptors of excitatory synapses. J Neurophysiol 80:3336–3340;1998.Google Scholar
  13. 13.
    Bergeron R, Meyer TM, Coyle JT, Greene RW. Modulation of N-methyl-D-aspartate receptor function by glycine transport. Proc Natl Acad Sci USA 95:15730–15734;1998.Google Scholar
  14. 14.
    Borden LA. GABA transporter heterogeneity: Pharmacology and cellular localization. Neurochem Int 29:335–356;1996.Google Scholar
  15. 15.
    Borowsky B, Mezey E, Hoffman BJ. Two glycine transporter variants with distinct localization in CNS and peripheral tissues are encoded by a common gene. Neuron 10:851–863;1993.Google Scholar
  16. 16.
    Chamberlain LH, Burgoyne RD. Cysteinestring protein: The chaperone at the synapse. J Neurochem 74:1781–1789;2000.Google Scholar
  17. 17.
    Chaudhry FA, Reimer RJ, Bellocchio EE, Danbolt NC, Osen KK, Edwards RH, Storm-Mathisen J. The vesicular GABA transporter, VGAT, localizes to synaptic vesicles in sets of glycinergic as well as GABAergic neurons. J Neurosci 18:9733–9750;1998.Google Scholar
  18. 18.
    Chen J, Zhu Y, Hu M. Mechanisms and kinetics of uptake and efflux of L-methionine in an intestinal epithelial model (Caco-2). J Nutr 124:1907–1916;1994.Google Scholar
  19. 19.
    Cho YD, Martin RO, Tunnicliff G, Uptake of [3H]glycine and [14C]glutamate by cultures of chick spinal cord. J Physiol 235:437–446;1973.Google Scholar
  20. 20.
    Christensen H, Fyske EM, Fonnum F. Uptake of glycine into synaptic vesicles isolated from rat spinal cord. J Neurochem 54:1142–1147;1990.Google Scholar
  21. 21.
    Christensen H, Fyske EM, Fonnum F. Inhibition of γ-aminobutyric acid and glycine uptake into synaptic vesicles. Eur J Pharmacol 207:73–79;1991.Google Scholar
  22. 22.
    Christie GR, Ford D, Howard A, Clark MA, Hirst BH. Glycine supply to human enterocytes mediated by high-affinity basolateral GLYT1. Gastroenterology 120:439–448;2001.Google Scholar
  23. 23.
    Dumoulin A, Rostaing P, Bedet C, Levi S, Isambert MF, Henry JP, Triller A, Gasnier B. Presence of the vesicular inhibitory amino acid transporter in GABAergic and glycinergic synaptic terminal boutons. J Cell Sci 112:811–823;1999.Google Scholar
  24. 24.
    Ellory JC, Jones SEM, Young JD. Glycine transport in human erythrocytes. J Physiol 320:403–422;1981.Google Scholar
  25. 25.
    Fernandez-Chacon R, Konigstorfer A, Gerber SH, Garcia J, Matos MF, Stevens CF, Brose N, Rizo J, Rosenmund C, Sudhof TC. Synaptotagmin I functions as a calcium regulator of release probability. Nature 410:41–49;2001.Google Scholar
  26. 26.
    Fernandez-Chacon R, Südhof TC. Genetics of synaptic vesicle function: Toward the complete functional anatomy of an organelle. Annu Rev Physiol 61:753–776;1999.Google Scholar
  27. 27.
    Fincham DA, Mason DK, Young JD. Characterization of a novel Na+-independent amino acid transporter in horse erythrocytes. Biochem J 227:13–20;1985.Google Scholar
  28. 28.
    Fremeau RT, Caron MG, Blakely RD. Molecular cloning and expression of a high affinity L-proline transporter expressed in putative glutamatergic pathways of rat brain. Neuron 8:915–926;1992.Google Scholar
  29. 29.
    Fukasawa Y, Segawa H, Kim JY, Chairoungdua A, Kim DK, Matsuc H, Cha SH, Endou H, Kanai Y. Identification and characterization of a Na+-independent neutral amino acid transporter that associates with the 4F2 heavy chain and exhibits substrate selectivity for small neutral D- and L-amino acids. J Biol Chem 275:9690–9698;2000.Google Scholar
  30. 30.
    Galietta LJV, Musante L, Caruso U, Fantasia A, Gazzolo A, Romano L, Sacco O, Rossi GA, Varesio L, Zegarra-Moran O. An electrogenic amino acid transporter in the apical membrane of cultured human bronchial epithelial cells. Am J Physiol 275:L917-L923;1998.Google Scholar
  31. 31.
    Gasnier B. The loading of neurotransmitters into synaptic vesicles. Biochimic 82:327–337;2000.Google Scholar
  32. 32.
    Geerlings A, Nuñez E, López-Corcuera B, Aragón C. Calcium- and syntaxin 1-mediated trafficking of the neuronal glycine transporter GLYT2. J Biol Chem 276:17584–17590;2001.Google Scholar
  33. 33.
    Graham LJ, Shank RP, Werman R, Aprison MH. Distribution of some synaptic transmitter suspects in cat spinal cord: Glutamic acid, aspartic acid, γ-aminobutyric acid, glycine and glutamine. J Neurochem 14:465–472;1967.Google Scholar
  34. 34.
    Guastella J, Brecha N, Weigmann C, Lester HA, Davidson N. Cloning, expression and localization of a rat brain high-affinity glycine transporter. Proc Natl Acad Sci USA 89:7189–7193;1992.Google Scholar
  35. 35.
    Hanley JG, Jones EMC, Moss SJ. GABA receptor rhol subunit interacts with a novel splice variant of the glycine transporter GLYT1. J Biol Chem 275:840–846;2000.Google Scholar
  36. 36.
    Hanson PI, Heuser JE, Jahn R. Neurotransmitter release — four years of SNARE complexes. Curr Opin Neurobiol 7:310–315;1997.Google Scholar
  37. 37.
    Herdon HJ, Godfrey FM, Brown AM, Coulton S, Evans JR, Cairns WJ. Pharmacological assessment of the role of the glycine transporter GlyT-1 in mediating high-affinity glycine uptake by rat cerebral cortex and cerebellum synaptosomes. Neuropharmacology 41:88–96;2001.Google Scholar
  38. 38.
    Johnson JW, Ascher P. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325:529–531;1987.Google Scholar
  39. 39.
    Johnston GAR, Iversen LL. Glycine uptake in rat central nervous system slices and homogenates: Evidence for different uptake systems in spinal cord and cerebral cortex. J Neurochem 18:1951–1961;1971.Google Scholar
  40. 40.
    Jonas P, Bischofberger J, Sandküler J. Corelease of two fast neurotransmitters at a central synapse. Science 281:419–424;1998.Google Scholar
  41. 41.
    Kanai Y, Segawa H, Miyamoto K, Uchino H, Takeda E, Endou H. Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). J Biol Chem 273:23629–23632;1998.Google Scholar
  42. 42.
    Kilberg MS, Stevens BR, Novak DA. Recent advances in mammalian amino acid transport. Annu Rev Nutr 13:137–165;1993.Google Scholar
  43. 43.
    Kim KM, Kingsmore SF, Han H, Yang-Feng TL, Godinot N, Seldin MF, Caron MG, Giros B. 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 45:608–617;1994.Google Scholar
  44. 44.
    King PA, Gunn RB. Glycine transport by human red blood cells and ghosts: Evidence for glycine anion and proton cotransport by band 3. Am J Physiol 261:C814-C821;1991.Google Scholar
  45. 45.
    Knauf PA. Erythrocyte anion exchange and the band 3 protein: Transport kinetics and molecular structure. Curr Top Membr Trans 12:249–263;1979.Google Scholar
  46. 46.
    Levi G, Raiteri M. Carrier-mediated release of neurotransmitters. Trends Neurosci 16:415–419;1993.Google Scholar
  47. 47.
    Liu Q-R, López-Corcuera B, Mandiyan S, Nelson H, Nelson N. Cloning and expression of a spinal cord and brain specific glycine transporter with novel structural features. J Biol Chem 268:22802–22808;1993.Google Scholar
  48. 48.
    Liu Q-R, Nelson H, Mandiyan S, López-Corcuera B, Nelson N. Cloning and expression of a glycine transporter from mouse brain. FEBS Lett 305:110–114;1992.Google Scholar
  49. 49.
    Logan WJ, Snyder SH. Unique high affinity uptake systems for glycine, glutamic and aspartic acids in central nervous tissue of the rat. Nature 234:297–299;1971.Google Scholar
  50. 50.
    López-Corcuera B, Geerlins A, Aragón C. Glycine neurotransmitter transporters: An update. Mol Membr Biol 18:13–20;2001.Google Scholar
  51. 51.
    López-Corcuera B, Kanner BI, Aragón C. Reconstitution and partial purification of the sodium-and chloride-coupled glycine transporter from rat spinal cord. Biochim Biophys Acta 983:247–252;1989.Google Scholar
  52. 52.
    López-Corcuera B, Vázquez J, Aragón C. Purification of the sodium- and chloride-coupled glycine transporter from central nervous system. J Biol Chem 266:24809–24814;1991.Google Scholar
  53. 53.
    Luque JM, Nelson N, Richards JG. Cellular expression of glycine transporter 2 messenger RNA exclusively in rat hindbrain and spinal cord. Neuroscience 64:525–535;1995.Google Scholar
  54. 54.
    McIntire SL, Reimer RJ, Schuske K, Edwards RH, Jorgensen EM. Identification and characterization of the vesicular GABA transporter. Nature 389:870–876;1997.Google Scholar
  55. 55.
    Muller CM, Viry S, Miehe M, Andriamampandry C, Aunis D, Maitre M. Evidence for a γ-hydroxybutyrate (GHB)uptake by rat brain synaptic vesicles. J Neurochem 80:899–904;2002.Google Scholar
  56. 56.
    Munck LK, Munck BG. Amino acid transport in the small intestine. Physiol Res 43:335–346;1994.Google Scholar
  57. 57.
    Munck LK, Munck BG. Transport of glycine and lysine on the chloride-dependent β-alanine B0+ carrier in rabbit small intestine. Biochim Biophys Acta 1235:93–99;1995.Google Scholar
  58. 58.
    Nuñez E, Aragón C. Structural analysis and functional role of the carbohydrate component of glycine transporter. J Biol Chem 269:16920–16924;1994.Google Scholar
  59. 59.
    Nuñez E, López-Corcuera B, Vazquez J, Giménez C, Aragón C. Differential effects of the tricyclic antidepressant amoxapine on glycine uptake mediated by the recombinant GLYT1 and GLYT2 glycine transporters. Br J Pharmacol 129:200–206;2000.Google Scholar
  60. 60.
    O'Brien JA, Berger AJ. Cotransmission of GABA and glycine to brain stem motorneurons. J Neurophysiol 82:1638–1641;1999.Google Scholar
  61. 61.
    Oxender DL, Christensen HN. Distinct mediating systems for the transport of neutral amino acids by the Ehrlich cell. J Biol Chem 238:3686–3699;1963.Google Scholar
  62. 62.
    Pineda M, Fernandez E, Torrents D, Estevez R, Lopez C, Camps M, Lloberas J, Zorzano A, Palacin M. Identification of a membrane protein, LAT-2, that co-expresses with 4F2 heavy chain, an L-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids. J Biol Chem 274:19738–19744;1999.Google Scholar
  63. 63.
    Ponce J, Poyatos I, Aragón C, Giménez C, Zafra F. Characterization of the 5′ region of the rat brain glycine transporter GLYT2 gene: Identification of a novel isoform. Neurosci Lett 242:25–28;1998.Google Scholar
  64. 64.
    Rossier G, Meier C, Bauch C, Summa V, Sordat B, Verrey F, Kühn LC. LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine. J Biol Chem 274:34948–34954;1999.Google Scholar
  65. 65.
    Roux M, Supplisson S. Neuronal and glial glycine transporters have different stoichiometries. Neuron 25:373–383;2000.Google Scholar
  66. 66.
    Sagné C, Mestikawy SE, Isambert MF, Hamon M, Henry JP, Giros B, Gasnier B. Cloning of a functional vesicular GABA and glycine transporter by screening of genome databases. FEBS Lett 417:177–183;1997.Google Scholar
  67. 67.
    Sakata K, Sato K, Schloss P, Betz H, Shimada S, Tohyama M. Characterization of glycine release mediated by glycine transporter 1 stably expressed in HEK-293 cells. Brain Res Mol Brain Res 49:89–94;1997.Google Scholar
  68. 68.
    Segawa H, Fukasawa Y, Miyamoto K, Takeda E, Endout H, Kanai Y. Identification and functional characterization of a Na+-independent neutral amino acid transporter with broad substrate selectivity. J Biol Chem 274:19745–19751;1999.Google Scholar
  69. 69.
    Sloan JL, Mager S. Cloning and functional expression of a human Na+-and Cl-dependent neutral and cationic amino acid transporter B0+. J Biol Chem 274:236740–23745;1999.Google Scholar
  70. 70.
    Smith KE, Borden LA, Harting PR, Branchek T, Weinshank RL. Cloning and expression of a glycine transporter reveal colocalization with NMDA receptors. Neuron 8:927–935;1992.Google Scholar
  71. 71.
    Snyder SH, Kim RM. D-Amino acids as putative neurotransmitters: Focus on D-serine. Neurochem Res 25:553–560;2000.Google Scholar
  72. 72.
    Stevens BR, Ross HJ, Wright E. Multiple transport pathways for neutral amino acids in rabbit jejunal brush border vesicles. J Membr Biol 66:213–225;1982.Google Scholar
  73. 73.
    Stevens BR, Ross HJ, Wright E. Intestinal transport of amino acids and sugars: Advances using membrane vesicles. Annu Rev Physiol 46:417–433;1984.Google Scholar
  74. 74.
    Tunnicliff G. Amino acid transport by human erythrocyte membranes. Comp Biochem Physiol Comp Physiol 108A:471–478;1994.Google Scholar
  75. 75.
    Tunnicliff G, Cash CD, eds. Gamma-Hydroxybutyrate: Molecular, Functional and Clinical Aspects. London, Taylor and Francis, 2002.Google Scholar
  76. 76.
    Tunnicliff G, Raess BU. γ-Hydroxybutyrate (orphan medical). Curr Opin Investig Drugs 3:278–283;2002.Google Scholar
  77. 77.
    Ugawa S, Sunouchi Y, Ueda T, Takahashi E, Saishin Y, Shimada S. Characterization of a mouse colonic system B0+ amino acid transporter related to amino acid absorption in colon. Am J Physiol 281:G365-G370;2001.Google Scholar
  78. 78.
    Utsunomiya-Tate N, Endou H, Kanai Y. Cloning and functional characterization of a system ASC-like Na+-dependent neutral amino acid transporter. J Biol Chem 271:14883–14890;1996.Google Scholar
  79. 79.
    Van Winkle LJ, Christensen HN, Campione AL. Na+-dependent transport of basic, zwitterionic, and bicyclic amino acids by a broadscope system in mouse blastocysts. J Biol Chem 260:12118–12123;1985.Google Scholar
  80. 80.
    Villalobos C, Nunez L, Garcia-Sancho J. Mechanisms for stimulation of rat anterior pituitary cells by arginine and other amino acids. J Physiol 502:421–431;1997.Google Scholar
  81. 81.
    Werman R, Davidoff RA, Aprison MH. Inhibition of motoneurones by iontophoresis of glycine. Nature 214:681–683;1967.Google Scholar
  82. 82.
    Wolf TR, Lance RA, Hart ER, Tunnicliff G. Uptake of [3H]glycine by synaptosomes of channel catfish brain. Arch Physiol Biochem 107:84–90;1999.Google Scholar
  83. 83.
    Yanagida O, Kanai Y, Chairoungdua A, Kim DK, Segawa H, Nii T, Cha SH, Matsuo H, Fukushima J, Fukasawa Y, Tani Y, Taketani Y, Uchino H, Kim JY, Inatomi J, Okayasu I, Miyamoto K, Takeda E, Goya T, Endou H. Human L-type amino acid transporter 1 (LAT1): Characterization of function and expression in tumor cell lines. Biochim Biophys Acta 1514:291–302;2001.Google Scholar
  84. 84.
    Young JD, Ellory JC. Red cell amino acid transport. In: Ellory JC, Lew VL, eds. Membrane Transport in Red Cells. London, Academic, 301–325;1977.Google Scholar
  85. 85.
    Young JD, Jones SEM, Ellory JC. Amino acid transport in human and sheep erythrocytes. Proc R Soc Lond B Biol Sci 209:355–375;1980.Google Scholar
  86. 86.
    Zafra F, Aragón C, Olivares L, Donbolt NC, Giménez C, Storm-Mathisen J. Glycine transporters are differentially expressed among CNS cells. J Neurosci 15:3952–3969;1995.Google Scholar
  87. 87.
    Zafra F, Gomeza J, Olivares L, Aragón C, Giménez C. Regional distribution and development variation of the glycine transporters GLYT1 and GLYT2 in the rat CNS. Eur J Neurosci 7:1342–1352;1995.Google Scholar

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© National Science Council 2003

Authors and Affiliations

  • Godfrey Tunnicliff
    • 1
  1. 1.Department of Biochemistry and Molecular BiologyIndiana Univeristy School of MedicineEvansvilleUSA

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