[{"@context":"http:\/\/schema.org\/","@type":"BlogPosting","@id":"https:\/\/wiki.edu.vn\/en\/wiki24\/gaba-transporter-type-1-wikipedia\/#BlogPosting","mainEntityOfPage":"https:\/\/wiki.edu.vn\/en\/wiki24\/gaba-transporter-type-1-wikipedia\/","headline":"GABA transporter type 1 – Wikipedia","name":"GABA transporter type 1 – Wikipedia","description":"From Wikipedia, the free encyclopedia Protein-coding gene in the species Homo sapiens GABA transporter 1 (GAT1) also known as sodium-","datePublished":"2018-04-02","dateModified":"2018-04-02","author":{"@type":"Person","@id":"https:\/\/wiki.edu.vn\/en\/wiki24\/author\/lordneo\/#Person","name":"lordneo","url":"https:\/\/wiki.edu.vn\/en\/wiki24\/author\/lordneo\/","image":{"@type":"ImageObject","@id":"https:\/\/secure.gravatar.com\/avatar\/c9645c498c9701c88b89b8537773dd7c?s=96&d=mm&r=g","url":"https:\/\/secure.gravatar.com\/avatar\/c9645c498c9701c88b89b8537773dd7c?s=96&d=mm&r=g","height":96,"width":96}},"publisher":{"@type":"Organization","name":"Enzyklop\u00e4die","logo":{"@type":"ImageObject","@id":"https:\/\/wiki.edu.vn\/wiki4\/wp-content\/uploads\/2023\/08\/download.jpg","url":"https:\/\/wiki.edu.vn\/wiki4\/wp-content\/uploads\/2023\/08\/download.jpg","width":600,"height":60}},"image":{"@type":"ImageObject","@id":"https:\/\/en.wikipedia.org\/wiki\/Special:CentralAutoLogin\/start?type=1x1","url":"https:\/\/en.wikipedia.org\/wiki\/Special:CentralAutoLogin\/start?type=1x1","height":"1","width":"1"},"url":"https:\/\/wiki.edu.vn\/en\/wiki24\/gaba-transporter-type-1-wikipedia\/","wordCount":9835,"articleBody":"From Wikipedia, the free encyclopediaProtein-coding gene in the species Homo sapiensGABA 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]Table of ContentsStructure[edit]Function[edit]Translocation cycle[edit]Clinical significance[edit]Interactions[edit]See also[edit]References[edit]Further reading[edit]Structure[edit]GAT1 is a 599 amino acid protein that consists of 12 transmembrane domains with an intracellular N-terminus and C-terminus.[10][8]Function[edit]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).[11][12] GABA Transporter 1 uses energy from the dissipation of a Na+ gradient, aided by the presence of a Cl\u2212 gradient, to translocate GABA across CNS neuronal membranes. The stoichiometry for GABA Transporter 1 is 2 Na+: 1 Cl\u2212: 1 GABA.[13] The presence of a Cl\u2212\/Cl\u2212 exchange is also proposed because the Cl\u2212 transported across the membrane does not affect the net charge.[14] GABA is also the primary inhibitory neurotransmitter in the cerebral cortex and has the highest level of expression within it.[15] The GABA affinity (Km) of the mouse isoform of GAT1 is 8 \u03bcM.[16]In the brain of a mature mammal, glutamate is converted to GABA by the enzyme glutamate decarboxylase (GAD) along with the addition of vitamin B6. GABA is then packed and released into the post-synaptic terminals of neurons after synthesis. GABA can also be used to form succinate, which is involved in the citric acid cycle.[17][10] Vesicle uptake has been shown to prioritize newly synthesized GABA over preformed GABA, though the reasoning behind this mechanism is currently not completely understood.The regulation of the modular functioning of GATs is highly dependent on a multitude of second messengers and synaptic proteins.[10]Translocation cycle[edit]Throughout the translocation cycle, GAT1 assumes three different conformations:Open-to-out. In this conformation, 2 extracellular Na+ ions are co-transported into the neuron along with 1 GABA and 1 Cl\u2212 that bind to the empty transporter, thus making it fully loaded. In prokaryotes, it has been found that transport does not require Cl\u2212. In mammals, the Cl\u2212 ion is required to offset the positive charge of the Na+ in order to maintain the proper membrane potential.[10]Occluded-out. Once fully loaded, this conformation prevents the release of ions\/substrate into the cytoplasm or the extracellular space\/synapse. The Na+, Cl\u2212, and GABA are bound to the transporter until it changes conformation.[10]Open-to-in. The transporter, which was previously facing the synapse, becomes inward facing and can now release the ions and GABA into the neuron’s cytoplasm. Once empty, the transporter occludes its binding site and flips to become outward facing so a new translocation cycle can begin.[10]Clinical significance[edit]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] GABA and its precursor glutamate have opposite functions within the nervous system. Glutamate is considered an excitatory neurotransmitter, while GABA is an inhibitory neurotransmitter. Glutamate and GABA imbalances contribute to different neurological pathologies..[17]Imbalance in the GABAergic neurotransmission is involved in the pathophysiology of various neurological diseases such as epilepsy, Alzheimer’s and stroke.[20]A study on genetic absence epilepsy rats from Strasbourg (GAERS) found that poor GABA uptake by GAT1 caused an increase in tonic current of GABAA. In the two most understood forms of absence epilepsy, synaptic GABAA receptors including GAT1 play a major role in seizure development. Blocking GAT1 in non-epileptic control (NEC) rats caused tonic current to increase to a rate similar to that of GAERS of the same age. This common cellular control site shows a possible target for future seizure treatments.[21]Glutamate and GABA have also been found to interact within the nucleus tractus solitarii (NTS), paraventricular nucleus (PVN), and rostral ventrolateral medulla (RVLM) of the brain to modulate blood pressure.[22]Interactions[edit]SLC6A1 has been shown to interact with STX1A.[23][24][25]See also[edit]References[edit]^ a b c GRCh38: Ensembl release 89: ENSG00000157103 – Ensembl, May 2017^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030310 – Ensembl, May 2017^ “Human PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.^ “Mouse PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.^ 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\u2013304. doi:10.1006\/geno.1995.1253. PMID\u00a08530094.^ “Entrez Gene: SLC6A1 solute carrier family 6 (neurotransmitter transporter, GABA), member 1”.^ Scimemi A (2014). “Structure, function, and plasticity of GABA transporters”. Frontiers in Cellular Neuroscience. 8: 161. doi:10.3389\/fncel.2014.00161. PMC\u00a04060055. PMID\u00a024987330.^ a b Gonzalez-Burgos G (2010). “GABA transporter GAT1: a crucial determinant of GABAB receptor activation in cortical circuits?”. GABABReceptor Pharmacology – A Tribute to Norman Bowery. Advances in Pharmacology. Vol.\u00a058. pp.\u00a0175\u2013204. doi:10.1016\/S1054-3589(10)58008-6. ISBN\u00a09780123786470. PMID\u00a020655483.^ Johannesen KM, Gardella E, Linnankivi T, Courage C, de Saint Martin A, Lehesjoki AE,  et\u00a0al. (February 2018). “Defining the phenotypic spectrum of SLC6A1 mutations”. Epilepsia. 59 (2): 389\u2013402. doi:10.1111\/epi.13986. PMC\u00a05912688. PMID\u00a029315614.^ a b c d e f Zafar S, Jabeen I (2018). “Structure, Function, and Modulation of \u03b3-Aminobutyric Acid Transporter 1 (GAT1) in Neurological Disorders: A Pharmacoinformatic Prospective”. Frontiers in Chemistry. 6: 397. Bibcode:2018FrCh….6..397Z. doi:10.3389\/fchem.2018.00397. PMC\u00a06141625. PMID\u00a030255012.^ Hirunsatit R, George ED, Lipska BK, Elwafi HM, Sander L, Yrigollen CM,  et\u00a0al. (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\u201365. doi:10.1097\/FPC.0b013e328318b21a. PMC\u00a02791799. PMID\u00a019077666.^ Madsen KK, Hansen GH, Danielsen EM, Schousboe A (February 2015). “The subcellular localization of GABA transporters and its implication for seizure management”. Neurochemical Research. 40 (2): 410\u2013419. doi:10.1007\/s11064-014-1494-9. PMID\u00a025519681. S2CID\u00a019008879.^ 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\u00a03148782. PMID\u00a021847373.^ Loo DD, Eskandari S, Boorer KJ, Sarkar HK, Wright EM (December 2000). “Role of Cl- in electrogenic Na+-coupled cotransporters GAT1 and SGLT1”. The Journal of Biological Chemistry. 275 (48): 37414\u201337422. doi:10.1074\/jbc.M007241200. PMID\u00a010973981.^ Conti F, Minelli A, Melone M (July 2004). “GABA transporters in the mammalian cerebral cortex: localization, development and pathological implications”. Brain Research. Brain Research Reviews. 45 (3): 196\u2013212. doi:10.1016\/j.brainresrev.2004.03.003. PMID\u00a015210304. S2CID\u00a019003675.^ Zhou Y, Danbolt NC (2013). “GABA and Glutamate Transporters in Brain”. Frontiers in Endocrinology. 4: 165. doi:10.3389\/fendo.2013.00165. PMC\u00a03822327. PMID\u00a024273530.^ a b Allen MJ, Sabir S, Sharma S (2022). “GABA Receptor”. StatPearls. Treasure Island (FL): StatPearls Publishing. PMID\u00a030252380. Retrieved 2022-04-11.^ 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\u2013265. doi:10.1176\/appi.ajp.158.2.256. PMID\u00a011156808.^ Hashimoto T, Matsubara T, Lewis DA (2010). “[Schizophrenia and cortical GABA neurotransmission]”. Seishin Shinkeigaku Zasshi = Psychiatria et Neurologia Japonica. 112 (5): 439\u2013452. PMID\u00a020560363.^ Kickinger S, Hellsberg E, Fr\u00f8lund B, Schousboe A, Ecker GF, Wellendorph P (December 2019). “Structural and molecular aspects of betaine-GABA transporter 1 (BGT1) and its relation to brain function”. Neuropharmacology. Neurotransmitter Transporters. 161: 107644. doi:10.1016\/j.neuropharm.2019.05.021. PMID\u00a031108110. S2CID\u00a0156055973.^ Cope DW, Di Giovanni G, Fyson SJ, Orb\u00e1n G, Errington AC, Lorincz ML,  et\u00a0al. (December 2009). “Enhanced tonic GABAA inhibition in typical absence epilepsy”. Nature Medicine. 15 (12): 1392\u20131398. doi:10.1038\/nm.2058. PMC\u00a02824149. PMID\u00a019966779.^ Dupont AG, L\u00e9gat L (October 2020). “GABA is a mediator of brain AT1 and AT2 receptor-mediated blood pressure responses”. Hypertension Research. 43 (10): 995\u20131005. doi:10.1038\/s41440-020-0470-9. PMID\u00a032451494. S2CID\u00a0218864718.^ 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\u20136112. doi:10.1523\/JNEUROSCI.18-16-06103.1998. PMC\u00a06793212. PMID\u00a09698305.^ 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\u20135691. Bibcode:2002PNAS…99.5686Q. doi:10.1073\/pnas.082712899. PMC\u00a0122832. PMID\u00a011960023.^ 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\u20131003. doi:10.1038\/79939. PMID\u00a011017172. S2CID\u00a011312913.Further reading[edit]Nelson H, Mandiyan S, Nelson N (August 1990). “Cloning of the human brain GABA transporter”. FEBS Letters. 269 (1): 181\u2013184. doi:10.1016\/0014-5793(90)81149-I. PMID\u00a02387399. S2CID\u00a034636220.Bennett ER, Kanner BI (January 1997). “The membrane topology of GAT-1, a (Na+ + Cl-)-coupled gamma-aminobutyric acid transporter from rat brain”. The Journal of Biological Chemistry. 272 (2): 1203\u20131210. doi:10.1074\/jbc.272.2.1203. PMID\u00a08995422.Bismuth Y, Kavanaugh MP, Kanner BI (June 1997). “Tyrosine 140 of the gamma-aminobutyric acid transporter GAT-1 plays a critical role in neurotransmitter recognition”. The Journal of Biological Chemistry. 272 (26): 16096\u201316102. doi:10.1074\/jbc.272.26.16096. PMID\u00a09195904.DeFelipe J, Gonz\u00e1lez-Albo MC (February 1998). “Chandelier cell axons are immunoreactive for GAT-1 in the human neocortex”. NeuroReport. 9 (3): 467\u2013470. doi:10.1097\/00001756-199802160-00020. PMID\u00a09512391. S2CID\u00a027446580.Conti F, Melone M, De Biasi S, Minelli A, Brecha NC, Ducati A (June 1998). “Neuronal and glial localization of GAT-1, a high-affinity gamma-aminobutyric acid plasma membrane transporter, in human cerebral cortex: with a note on its distribution in monkey cortex”. The Journal of Comparative Neurology. 396 (1): 51\u201363. doi:10.1002\/(SICI)1096-9861(19980622)396:13.0.CO;2-H. PMID\u00a09623887. S2CID\u00a033438310.Augood SJ, Waldvogel HJ, M\u00fcnkle MC, Faull RL, Emson PC (January 1999). “Localization of calcium-binding proteins and GABA transporter (GAT-1) messenger RNA in the human subthalamic nucleus”. Neuroscience. 88 (2): 521\u2013534. doi:10.1016\/S0306-4522(98)00226-7. PMID\u00a010197772. S2CID\u00a02514970.Ong WY, Yeo TT, Balcar VJ, Garey LJ (October 1998). “A light and electron microscopic study of GAT-1-positive cells in the cerebral cortex of man and monkey”. Journal of Neurocytology. 27 (10): 719\u2013730. doi:10.1023\/A:1006946717065. PMID\u00a010640187. S2CID\u00a039552099.Whitworth TL, Quick MW (November 2001). “Substrate-induced regulation of gamma-aminobutyric acid transporter trafficking requires tyrosine phosphorylation”. The Journal of Biological Chemistry. 276 (46): 42932\u201342937. doi:10.1074\/jbc.M107638200. PMID\u00a011555659.Hachiya Y, Takashima S (November 2001). “Development of GABAergic neurons and their transporter in human temporal cortex”. Pediatric Neurology. 25 (5): 390\u2013396. doi:10.1016\/S0887-8994(01)00348-4. PMID\u00a011744314.Kanner BI (February 2003). “Transmembrane domain I of the gamma-aminobutyric acid transporter GAT-1 plays a crucial role in the transition between cation leak and transport modes”. The Journal of Biological Chemistry. 278 (6): 3705\u20133712. doi:10.1074\/jbc.M210525200. PMID\u00a012446715.Zomot E, Kanner BI (October 2003). “The interaction of the gamma-aminobutyric acid transporter GAT-1 with the neurotransmitter is selectively impaired by sulfhydryl modification of a conformationally sensitive cysteine residue engineered into extracellular loop IV”. The Journal of Biological Chemistry. 278 (44): 42950\u201342958. doi:10.1074\/jbc.M209307200. PMID\u00a012925537.Zhou Y, Bennett ER, Kanner BI (April 2004). “The aqueous accessibility in the external half of transmembrane domain I of the GABA transporter GAT-1 Is modulated by its ligands”. The Journal of Biological Chemistry. 279 (14): 13800\u201313808. doi:10.1074\/jbc.M311579200. PMID\u00a014744863.Hu JH, Ma YH, Jiang J, Yang N, Duan SH, Jiang ZH,  et\u00a0al. (January 2004). “Cognitive impairment in mice over-expressing gamma-aminobutyric acid transporter 1 (GAT1)”. NeuroReport. 15 (1): 9\u201312. doi:10.1097\/00001756-200401190-00003. PMID\u00a015106822. S2CID\u00a06407617.Korkhov VM, Farhan H, Freissmuth M, Sitte HH (December 2004). “Oligomerization of the {gamma}-aminobutyric acid transporter-1 is driven by an interplay of polar and hydrophobic interactions in transmembrane helix II”. The Journal of Biological Chemistry. 279 (53): 55728\u201355736. doi:10.1074\/jbc.M409449200. PMID\u00a015496410.This article incorporates text from the United States National Library of Medicine, which is in the public domain.  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