GABA transporter type 1

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SLC6A1
Identifiers
AliasesSLC6A1, GABATHG, GABATR, GAT1, MAE, GABA transporter 1, solute carrier family 6 member 1
External IDsOMIM: 137165; MGI: 95627; HomoloGene: 2290; GeneCards: SLC6A1; OMA:SLC6A1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6529

232333

Ensembl

ENSG00000157103

ENSMUSG00000030310

UniProt

P30531

P31648

RefSeq (mRNA)

NM_003042
NM_001348250
NM_001348251
NM_001348252
NM_001348253

NM_178703

RefSeq (protein)

NP_003033
NP_001335179
NP_001335180
NP_001335181
NP_001335182

NP_848818

Location (UCSC)Chr 3: 10.99 – 11.04 MbChr 6: 114.26 – 114.29 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

GABA transporter 1 (GAT1) also known as sodium- and chloride-dependent GABA transporter 1 is a protein that in humans is encoded by the SLC6A1 gene and belongs to the solute carrier 6 (SLC6) family of transporters.[5][6][7] It mediates gamma-aminobutyric acid's translocation from the extracellular to intracellular spaces within brain tissue and the central nervous system as a whole.[8][9]

Structure

GAT1 is a 599 amino acid protein that consists of 12 transmembrane domains with an intracellular N-terminus and C-terminus.[10][11]

File:GAT Membrane Topology and Structure.jpg
(A) Generalized GAT membrane topology. (B) hGAT1 three-dimensional structure including bound substrates.

Function

GAT1 is a gamma-aminobutyric acid (GABA) transporter, which removes GABA from the synaptic cleft by shuttling it to presynaptic neurons (where GABA can be recycled) and astrocytes (where GABA can be broken down).[12][13] GABA Transporter 1 uses energy from the dissipation of a Na+ gradient, aided by the presence of a Cl− gradient, to translocate GABA across CNS neuronal membranes. The stoichiometry for GABA Transporter 1 is 2 Na+: 1 Cl−: 1 GABA.[14] The presence of a Cl−/Cl− exchange is also proposed because the Cl− transported across the membrane does not affect the net charge.[15] GABA is also the primary inhibitory neurotransmitter in the cerebral cortex and has the highest level of expression within it.[16] The GABA affinity (Km) of the mouse isoform of GAT1 is 8 μM.[17]

Clinical significance

Research has shown that schizophrenia patients have GABA synthesis and expression altered, leading to the conclusion that GABA Transporter-1, which adds and removes GABA from the synaptic cleft, plays a role in the development of neurological disorders such as schizophrenia.[18][19]

Interactions

SLC6A1 has been shown to interact with STX1A.[20][21][22]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000157103 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030310 – 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. ^ Huang F, Shi LJ, Heng HH, Fei J, Guo LH (September 1995). "Assignment of the human GABA transporter gene (GABATHG) locus to chromosome 3p24-p25". Genomics. 29 (1): 302–4. doi:10.1006/geno.1995.1253. PMID 8530094.
  6. ^ "Entrez Gene: SLC6A1 solute carrier family 6 (neurotransmitter transporter, GABA), member 1".
  7. ^ Scimemi, Annalisa (2014). "Structure, function, and plasticity of GABA transporters". Frontiers in Cellular Neuroscience. 8. doi:10.3389/fncel.2014.00161/full. ISSN 1662-5102.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ Gonzalez-Burgos, Guillermo (2010). "GABA transporter GAT1: a crucial determinant of GABAB receptor activation in cortical circuits?". Advances in Pharmacology (San Diego, Calif.). 58: 175–204. doi:10.1016/S1054-3589(10)58008-6. ISSN 1557-8925. PMID 20655483.
  9. ^ Johannesen, Katrine M.; Gardella, Elena; Linnankivi, Tarja; Courage, Carolina; de Saint Martin, Anne; Lehesjoki, Anna-Elina; Mignot, Cyril; Afenjar, Alexandra; Lesca, Gaetan; Abi-Warde, Marie-Thérèse; Chelly, Jamel (2018-01-08). "Defining the phenotypic spectrum of SLC6A1 mutations". Epilepsia. 59 (2): 389–402. doi:10.1111/epi.13986. ISSN 0013-9580. PMC 5912688. PMID 29315614.
  10. ^ Zafar, Sadia; Jabeen, Ishrat (2018). "Structure, Function, and Modulation of γ-Aminobutyric Acid Transporter 1 (GAT1) in Neurological Disorders: A Pharmacoinformatic Prospective". Frontiers in Chemistry. 6. doi:10.3389/fchem.2018.00397/full#b81. ISSN 2296-2646.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  11. ^ Gonzalez-Burgos, Guillermo (2010). "GABA transporter GAT1: a crucial determinant of GABAB receptor activation in cortical circuits?". Advances in Pharmacology (San Diego, Calif.). 58: 175–204. doi:10.1016/S1054-3589(10)58008-6. ISSN 1557-8925. PMID 20655483.
  12. ^ Hirunsatit R, George ED, Lipska BK, Elwafi HM, Sander L, Yrigollen CM, Gelernter J, Grigorenko EL, Lappalainen J, Mane S, Nairn AC, Kleinman JE, Simen AA (January 2009). "Twenty-one-base-pair insertion polymorphism creates an enhancer element and potentiates SLC6A1 GABA transporter promoter activity". Pharmacogenetics and Genomics. 19 (1): 53–65. doi:10.1097/FPC.0b013e328318b21a. PMC 2791799. PMID 19077666.
  13. ^ Madsen, Karsten K.; Hansen, Gert H.; Danielsen, E. Michael; Schousboe, Arne (2015-02-01). "The Subcellular Localization of GABA Transporters and Its Implication for Seizure Management". Neurochemical Research. 40 (2): 410–419. doi:10.1007/s11064-014-1494-9. ISSN 1573-6903.
  14. ^ Jin XT, Galvan A, Wichmann T, Smith Y (28 July 2011). "Localization and Function of GABA Transporters GAT-1 and GAT-3 in the Basal Ganglia". Frontiers in Systems Neuroscience. 5: 63. doi:10.3389/fnsys.2011.00063. PMC 3148782. PMID 21847373.
  15. ^ Loo, Donald D. F.; Eskandari, Sepehr; Boorer, Kathryn J.; Sarkar, Hemanta K.; Wright, Ernest M. (2000-12-01). "Role of Cl− in Electrogenic Na+-coupled Cotransporters GAT1 and SGLT1 *". Journal of Biological Chemistry. 275 (48): 37414–37422. doi:10.1074/jbc.M007241200. ISSN 0021-9258. PMID 10973981.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  16. ^ Conti, Fiorenzo; Minelli, Andrea; Melone, Marcello (2004-07-01). "GABA transporters in the mammalian cerebral cortex: localization, development and pathological implications". Brain Research Reviews. 45 (3): 196–212. doi:10.1016/j.brainresrev.2004.03.003. ISSN 0165-0173.
  17. ^ Zhou, Yun; Danbolt, Niels (2013). "GABA and Glutamate Transporters in Brain". Frontiers in Endocrinology. 4. doi:10.3389/fendo.2013.00165/full. ISSN 1664-2392.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  18. ^ Volk D, Austin M, Pierri J, Sampson A, Lewis D (February 2001). "GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons". The American Journal of Psychiatry. 158 (2): 256–65. doi:10.1176/appi.ajp.158.2.256. PMID 11156808.
  19. ^ Hashimoto, T; Matsubara, T; Lewis, DA (2010). "[Schizophrenia and cortical GABA neurotransmission]". Seishin Shinkeigaku Zasshi = Psychiatria et Neurologia Japonica. 112 (5): 439–52. PMID 20560363.
  20. ^ Beckman ML, Bernstein EM, Quick MW (August 1998). "Protein kinase C regulates the interaction between a GABA transporter and syntaxin 1A". The Journal of Neuroscience. 18 (16): 6103–12. doi:10.1523/JNEUROSCI.18-16-06103.1998. PMC 6793212. PMID 9698305.
  21. ^ Quick MW (April 2002). "Substrates regulate gamma-aminobutyric acid transporters in a syntaxin 1A-dependent manner". Proceedings of the National Academy of Sciences of the United States of America. 99 (8): 5686–91. Bibcode:2002PNAS...99.5686Q. doi:10.1073/pnas.082712899. PMC 122832. PMID 11960023.
  22. ^ Deken SL, Beckman ML, Boos L, Quick MW (October 2000). "Transport rates of GABA transporters: regulation by the N-terminal domain and syntaxin 1A". Nature Neuroscience. 3 (10): 998–1003. doi:10.1038/79939. PMID 11017172. S2CID 11312913.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.


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