Sodium- and chloride-dependent glycine transporter 1 explained

Sodium- and chloride-dependent glycine transporter 1, also known as glycine transporter 1, is a protein that in humans is encoded by the SLC6A9 gene which is promising therapeutic target for treatment of diabetes and obesity. ^{[1] [2] [3] [4]}

Selective inhibitors

Elevation of extracellular synaptic glycine concentration by blockade of GlyT1 has been hypothesized to potentiate NMDA receptor function in vivo and to represent a rational approach for the treatment of schizophrenia and cognitive disorders. Several drug candidates have reached clinical trials.^[5]

• ASP2535^[6]
• Bitopertin (RG1678), which has entered phase II trials for the treatment of schizophrenia^[7]
• Iclepertin (BI 425809) by Boehringer Ingelheim which is thought to improve cognitive impairment due to schizophrenia
• Org 25935 (Sch 900435)
• PF-03463275 (in phase II trial)
• Pesampator (PF-04958242) by Pfizer
• Sarcosine which is thought to improve cognitive impairment due to schizophrenia

Pathological mutations

Mutations of the gene may cause a severe metabolic disorder discovered in 2016 and called glycine encephalopathy with normal serum glycine (OMIM 617301), also known as GlyT1 encephalopathy.

See also

• • Solute carrier family

Further reading

• Olivares L, Aragón C, Giménez C, Zafra F . The role of N-glycosylation in the targeting and activity of the GLYT1 glycine transporter . J. Biol. Chem. . 270 . 16 . 9437–42 . 1995 . 7721869 . 10.1074/jbc.270.16.9437 . free .
• Borowsky B, Mezey E, Hoffman BJ . Two glycine transporter variants with distinct localization in the CNS and peripheral tissues are encoded by a common gene . Neuron . 10 . 5 . 851–63 . 1993 . 8494645 . 10.1016/0896-6273(93)90201-2 . 24224402 .
• Evans J, Herdon H, Cairns W, etal . Cloning, functional characterisation and population analysis of a variant form of the human glycine type 2 transporter . FEBS Lett. . 463 . 3 . 301–6 . 2000 . 10606742 . 10.1016/S0014-5793(99)01636-1 . 21445629 .
• Hanley JG, Jones EM, Moss SJ . GABA receptor rho1 subunit interacts with a novel splice variant of the glycine transporter, GLYT-1 . J. Biol. Chem. . 275 . 2 . 840–6 . 2000 . 10625616 . 10.1074/jbc.275.2.840 . free .
• Geerlings A, López-Corcuera B, Aragón C . Characterization of the interactions between the glycine transporters GLYT1 and GLYT2 and the SNARE protein syntaxin 1A . FEBS Lett. . 470 . 1 . 51–4 . 2000 . 10722844 . 10.1016/S0014-5793(00)01297-7 . 46670631 .
• Christie GR, Ford D, Howard A, etal . Glycine supply to human enterocytes mediated by high-affinity basolateral GLYT1 . Gastroenterology . 120 . 2 . 439–48 . 2001 . 11159884 . 10.1053/gast.2001.21207 . free .
• Reye P, Penfold P, Pow DV . Glyt-1 expression in cultured human Müller cells and intact retinae . Glia . 34 . 4 . 311–5 . 2001 . 11360303 . 10.1002/glia.1064 . 39431701 .
• Geerlings A, Núñez E, Rodenstein L, etal . Glycine transporter isoforms show differential subcellular localization in PC12 cells . J. Neurochem. . 82 . 1 . 58–65 . 2002 . 12091465 . 10.1046/j.1471-4159.2002.00930.x . free .
• Brandenberger R, Wei H, Zhang S, etal . Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation . Nat. Biotechnol. . 22 . 6 . 707–16 . 2005 . 15146197 . 10.1038/nbt971 . 27764390 .
• Antonov SM, Brovtsyna NB, Mironova EV . The mechanism of allosteric interaction of cytoplasmic and extracellular Cl⁻ in the glial glycine transporter (hGlyTlb) . Dokl. Biol. Sci. . 402 . 1–6. 163–6 . 2005 . 16121932 . 10.1007/s10630-005-0076-z . 19628294 .

Notes and References

1. Sinha . Jitendra Kumar . Durgvanshi . Shantanu . Verma . Manish . Ghosh . Shampa . June 2023 . Investigation of SLC6A9 and SLC5A1 as a promising therapeutic target for obesity and diabetes using in silico characterization, 3D structure prediction and molecular docking analysis . Alzheimer's & Dementia . en . 19 . S1 . 10.1002/alz.064229 . 1552-5260. free .
2. 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 . 4 . 608–17 . Jun 1994 . 8183239 .
3. Jones EM, Fernald A, Bell GI, Le Beau MM . Assignment of SLC6A9 to human chromosome band 1p33 by in situ hybridization . Cytogenet Cell Genet . 71 . 3 . 211 . Nov 1995 . 7587377 . 10.1159/000134110.
4. Web site: Entrez Gene: SLC6A9 solute carrier family 6 (neurotransmitter transporter, glycine), member 9.
5. Glycine transporters as novel therapeutic targets in schizophrenia, alcohol dependence and pain. 31 October 2013. Nature Reviews Drug Discovery. 10.1038/nrd3893. 24172334. 12. 11. 866–85. Harvey. Robert J.. Yee. Benjamin K.. 28022131.
6. Harada K, Nakato K, Yarimizu J, Yamazaki M, Morita M, Takahashi S, Aota M, Saita K, Doihara H, Sato Y, Yamaji T, Ni K, Matsuoka N . 2012 . A novel glycine transporter-1 (GlyT1) inhibitor, ASP2535 (4-[3-isopropyl-5-(6-phenyl-3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzoxadiazole), improves cognition in animal models of cognitive impairment in schizophrenia and Alzheimer's disease . European Journal of Pharmacology . 685. 1–3. 59–69. 10.1016/j.ejphar.2012.04.013 . 22542656 .
7. Pinard E, Alanine A, Alberati D, Bender M, Borroni E, Bourdeaux P, Brom V, Burner S, Fischer H, Hainzl D, Halm R, Hauser N, Jolidon S, Lengyel J, Marty HP, Meyer T, Moreau JL, Mory R, Narquizian R, Nettekoven M, Norcross RD, Puellmann B, Schmid P, Schmitt S, Stalder H, Wermuth R, Wettstein JG, Zimmerli D . Selective GlyT1 inhibitors: discovery of [4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl][5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methylethoxy)phenyl]methanone (RG1678), a promising novel medicine to treat schizophrenia . J. Med. Chem. . 53 . 12 . 4603–14 . June 2010 . 20491477 . 10.1021/jm100210p .