Sodium- and chloride-dependent glycine transporter 1: Difference between revisions

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{{Short description|Protein-coding gene in the species Homo sapiens}}
{{PBB|geneid=6536}}
{{Infobox_gene}}
'''Sodium- and chloride-dependent glycine transporter 1''' is a [[protein]] that in humans is encoded by the ''SLC6A9'' [[gene]].<ref name="pmid8183239">{{cite journal | author = Kim KM, Kingsmore SF, Han H, Yang-Feng TL, Godinot N, Seldin MF, Caron MG, Giros B | title = 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 | journal = Mol Pharmacol | volume = 45 | issue = 4 | pages = 608–17 | year = 1994 | month = Jun | pmid = 8183239 | pmc = | doi = }}</ref><ref name="pmid7587377">{{cite journal | author = Jones EM, Fernald A, Bell GI, Le Beau MM | title = Assignment of SLC6A9 to human chromosome band 1p33 by in situ hybridization | journal = Cytogenet Cell Genet | volume = 71 | issue = 3 | pages = 211 | year = 1995 | month = Nov | pmid = 7587377 | pmc = | doi = 10.1159/000134110}}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SLC6A9 solute carrier family 6 (neurotransmitter transporter, glycine), member 9| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6536| accessdate = }}</ref>
'''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. <ref>{{Cite journal |last1=Sinha |first1=Jitendra Kumar |last2=Durgvanshi |first2=Shantanu |last3=Verma |first3=Manish |last4=Ghosh |first4=Shampa |date=June 2023 |title=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 |journal=Alzheimer's & Dementia |language=en |volume=19 |issue=S1 |doi=10.1002/alz.064229 |issn=1552-5260|doi-access=free }}</ref><ref name="pmid8183239">{{cite journal |vauthors=Kim KM, Kingsmore SF, Han H, Yang-Feng TL, Godinot N, Seldin MF, Caron MG, Giros B | title = 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 | journal = Mol Pharmacol | volume = 45 | issue = 4 | pages = 608–17 |date=Jun 1994 | pmid = 8183239 }}</ref><ref name="pmid7587377">{{cite journal |vauthors=Jones EM, Fernald A, Bell GI, Le Beau MM | title = Assignment of SLC6A9 to human chromosome band 1p33 by in situ hybridization | journal = Cytogenet Cell Genet | volume = 71 | issue = 3 | pages = 211 |date=Nov 1995 | pmid = 7587377 | doi = 10.1159/000134110}}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SLC6A9 solute carrier family 6 (neurotransmitter transporter, glycine), member 9| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6536}}</ref>


==Selective inhibitors==
==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.
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.<ref>{{Cite journal|title = Glycine transporters as novel therapeutic targets in schizophrenia, alcohol dependence and pain|date = 31 October 2013|journal = Nature Reviews Drug Discovery|doi = 10.1038/nrd3893|pmid = 24172334|volume=12|issue = 11|pages=866–85|last1 = Harvey|first1 = Robert J.|last2 = Yee|first2 = Benjamin K.|s2cid = 28022131}}</ref>
* [[ASP2535]]<ref>{{cite journal |vauthors=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 | year = 2012 | title = 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 | journal = European Journal of Pharmacology | volume = 685| issue = 1–3| pages = 59–69| doi = 10.1016/j.ejphar.2012.04.013 | pmid = 22542656 }}</ref>
⚫
* [[Bitopertin]] (RG1678), which has entered [[clinical trial#Phase II|phase II]] trials for the treatment of schizophrenia<ref name="pmid20491477">{{cite journal |vauthors=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 | title = 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 | journal = J. Med. Chem. | volume = 53 | issue = 12 | pages = 4603–14 |date=June 2010 | pmid = 20491477 | doi = 10.1021/jm100210p }}</ref>
* 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==
⚫
* RG1678 which has entered [[clinical trial#Phase II|phase II]] trials for the treatment of schizophrenia<ref name="pmid20491477">{{cite journal | author = 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 | title = 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 | journal = J. Med. Chem. | volume = 53 | issue = 12 | pages = 4603–14 | year = 2010 | month = June | pmid = 20491477 | doi = 10.1021/jm100210p | url = | issn = }}</ref>
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==
==See also==
Line 16: Line 25:
==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
⚫
*{{cite journal |vauthors=Olivares L, Aragón C, Giménez C, Zafra F |title=The role of N-glycosylation in the targeting and activity of the GLYT1 glycine transporter |journal=J. Biol. Chem. |volume=270 |issue= 16 |pages= 9437–42 |year= 1995 |pmid= 7721869 |doi=10.1074/jbc.270.16.9437 |doi-access=free }}
{{PBB_Further_reading
*{{cite journal |vauthors=Borowsky B, Mezey E, Hoffman BJ |title=Two glycine transporter variants with distinct localization in the CNS and peripheral tissues are encoded by a common gene |journal=Neuron |volume=10 |issue= 5 |pages= 851–63 |year= 1993 |pmid= 8494645 |doi=10.1016/0896-6273(93)90201-2 |s2cid=24224402 }}
| citations =
*{{cite journal | author=Olivares L, Aragón C, Giménez C, Zafra F |title=The role of N-glycosylation in the targeting and activity of the GLYT1 glycine transporter. |journal=J. Biol. Chem. |volume=270 |issue= 16 |pages= 9437–42 |year= 1995 |pmid= 7721869 |doi=10.1074/jbc.270.16.9437 }}
*{{cite journal |vauthors=Evans J, Herdon H, Cairns W, etal |title=Cloning, functional characterisation and population analysis of a variant form of the human glycine type 2 transporter |journal=FEBS Lett. |volume=463 |issue= 3 |pages= 301–6 |year= 2000 |pmid= 10606742 |doi=10.1016/S0014-5793(99)01636-1 |s2cid=21445629 |doi-access= }}
*{{cite journal | author=Borowsky B, Mezey E, Hoffman BJ |title=Two glycine transporter variants with distinct localization in the CNS and peripheral tissues are encoded by a common gene. |journal=Neuron |volume=10 |issue= 5 |pages= 851–63 |year= 1993 |pmid= 8494645 |doi=10.1016/0896-6273(93)90201-2 }}
*{{cite journal |vauthors=Hanley JG, Jones EM, Moss SJ |title=GABA receptor rho1 subunit interacts with a novel splice variant of the glycine transporter, GLYT-1 |journal=J. Biol. Chem. |volume=275 |issue= 2 |pages= 840–6 |year= 2000 |pmid= 10625616 |doi=10.1074/jbc.275.2.840 |doi-access=free }}
*{{cite journal | author=Evans J, Herdon H, Cairns W, ''et al.'' |title=Cloning, functional characterisation and population analysis of a variant form of the human glycine type 2 transporter. |journal=FEBS Lett. |volume=463 |issue= 3 |pages= 301–6 |year= 2000 |pmid= 10606742 |doi=10.1016/S0014-5793(99)01636-1 }}
*{{cite journal |vauthors=Geerlings A, López-Corcuera B, Aragón C |title=Characterization of the interactions between the glycine transporters GLYT1 and GLYT2 and the SNARE protein syntaxin 1A |journal=FEBS Lett. |volume=470 |issue= 1 |pages= 51–4 |year= 2000 |pmid= 10722844 |doi=10.1016/S0014-5793(00)01297-7 |s2cid=46670631 }}
*{{cite journal | author=Hanley JG, Jones EM, Moss SJ |title=GABA receptor rho1 subunit interacts with a novel splice variant of the glycine transporter, GLYT-1. |journal=J. Biol. Chem. |volume=275 |issue= 2 |pages= 840–6 |year= 2000 |pmid= 10625616 |doi=10.1074/jbc.275.2.840 }}
*{{cite journal |vauthors=Christie GR, Ford D, Howard A, etal |title=Glycine supply to human enterocytes mediated by high-affinity basolateral GLYT1 |journal=Gastroenterology |volume=120 |issue= 2 |pages= 439–48 |year= 2001 |pmid= 11159884 |doi=10.1053/gast.2001.21207 |doi-access=free }}
*{{cite journal | author=Geerlings A, López-Corcuera B, Aragón C |title=Characterization of the interactions between the glycine transporters GLYT1 and GLYT2 and the SNARE protein syntaxin 1A. |journal=FEBS Lett. |volume=470 |issue= 1 |pages= 51–4 |year= 2000 |pmid= 10722844 |doi=10.1016/S0014-5793(00)01297-7 }}
*{{cite journal |vauthors=Reye P, Penfold P, Pow DV |title=Glyt-1 expression in cultured human Müller cells and intact retinae |journal=Glia |volume=34 |issue= 4 |pages= 311–5 |year= 2001 |pmid= 11360303 |doi=10.1002/glia.1064 |s2cid=39431701 }}
*{{cite journal | author=Christie GR, Ford D, Howard A, ''et al.'' |title=Glycine supply to human enterocytes mediated by high-affinity basolateral GLYT1. |journal=Gastroenterology |volume=120 |issue= 2 |pages= 439–48 |year= 2001 |pmid= 11159884 |doi=10.1053/gast.2001.21207 }}
*{{cite journal |vauthors=Geerlings A, Núñez E, Rodenstein L, etal |title=Glycine transporter isoforms show differential subcellular localization in PC12 cells |journal=J. Neurochem. |volume=82 |issue= 1 |pages= 58–65 |year= 2002 |pmid= 12091465 |doi=10.1046/j.1471-4159.2002.00930.x |doi-access=free }}
*{{cite journal | author=Reye P, Penfold P, Pow DV |title=Glyt-1 expression in cultured human Müller cells and intact retinae. |journal=Glia |volume=34 |issue= 4 |pages= 311–5 |year= 2001 |pmid= 11360303 |doi=10.1002/glia.1064 }}
*{{cite journal |vauthors=Brandenberger R, Wei H, Zhang S, etal |title=Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation |journal=Nat. Biotechnol. |volume=22 |issue= 6 |pages= 707–16 |year= 2005 |pmid= 15146197 |doi= 10.1038/nbt971 |s2cid=27764390 }}
*{{cite journal | author=Geerlings A, Núñez E, Rodenstein L, ''et al.'' |title=Glycine transporter isoforms show differential subcellular localization in PC12 cells. |journal=J. Neurochem. |volume=82 |issue= 1 |pages= 58–65 |year= 2002 |pmid= 12091465 |doi=10.1046/j.1471-4159.2002.00930.x }}
*{{cite journal |vauthors=Antonov SM, Brovtsyna NB, Mironova EV |title=The mechanism of allosteric interaction of cytoplasmic and extracellular Cl<sup>−</sup> in the glial glycine transporter (hGlyTlb) |journal=Dokl. Biol. Sci. |volume=402 |issue= 1–6|pages= 163–6 |year= 2005 |pmid= 16121932 |doi=10.1007/s10630-005-0076-z |s2cid=19628294 }}
*{{cite journal | author=Brandenberger R, Wei H, Zhang S, ''et al.'' |title=Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation. |journal=Nat. Biotechnol. |volume=22 |issue= 6 |pages= 707–16 |year= 2005 |pmid= 15146197 |doi= 10.1038/nbt971 }}
⚫
*{{cite journal | author=Antonov SM, Brovtsyna NB, Mironova EV |title=The mechanism of allosteric interaction of cytoplasmic and extracellular Cl- in the glial glycine transporter (hGlyTlb). |journal=Dokl. Biol. Sci. |volume=402 |issue= |pages= 163–6 |year= 2005 |pmid= 16121932 |doi=10.1007/s10630-005-0076-z }}
}}
{{refend}}
{{refend}}


⚫
{{membrane-protein-stub}}
{{Membrane transport proteins}}
{{Membrane transport proteins}}
{{Glycinergics}}
{{Glycinergics}}
{{Glutamatergics}}


[[Category:Solute carrier family]]
[[Category:Solute carrier family]]



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Latest revision as of 15:54, 13 January 2024

SLC6A9
Identifiers
AliasesSLC6A9, GLYT1, Glycine transporter 1, solute carrier family 6 member 9, GCENSG
External IDsOMIM: 601019 MGI: 95760 HomoloGene: 5050 GeneCards: SLC6A9
Orthologs
SpeciesHumanMouse
Entrez

6536

14664

Ensembl

ENSG00000196517

ENSMUSG00000028542

UniProt

P48067

P28571

RefSeq (mRNA)

NM_008135
NM_001355175
NM_001369016
NM_001369017

RefSeq (protein)

NP_032161
NP_001342104
NP_001355945
NP_001355946

Location (UCSC)Chr 1: 43.99 – 44.03 MbChr 4: 117.69 – 117.73 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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. [5][6][7][8]

Selective inhibitors[edit]

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.[9]

  • ASP2535[10]
  • Bitopertin (RG1678), which has entered phase II trials for the treatment of schizophrenia[11]
  • 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[edit]

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[edit]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000196517 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028542 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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. 19 (S1). doi:10.1002/alz.064229. ISSN 1552-5260.
  6. ^ Kim KM, Kingsmore SF, Han H, Yang-Feng TL, Godinot N, Seldin MF, Caron MG, Giros B (Jun 1994). "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. PMID 8183239.
  7. ^ Jones EM, Fernald A, Bell GI, Le Beau MM (Nov 1995). "Assignment of SLC6A9 to human chromosome band 1p33 by in situ hybridization". Cytogenet Cell Genet. 71 (3): 211. doi:10.1159/000134110. PMID 7587377.
  8. ^ "Entrez Gene: SLC6A9 solute carrier family 6 (neurotransmitter transporter, glycine), member 9".
  9. ^ Harvey, Robert J.; Yee, Benjamin K. (31 October 2013). "Glycine transporters as novel therapeutic targets in schizophrenia, alcohol dependence and pain". Nature Reviews Drug Discovery. 12 (11): 866–85. doi:10.1038/nrd3893. PMID 24172334. S2CID 28022131.
  10. ^ 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. doi:10.1016/j.ejphar.2012.04.013. PMID 22542656.
  11. ^ 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 (June 2010). "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. doi:10.1021/jm100210p. PMID 20491477.

Further reading[edit]


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