GABA transporter type 1: Difference between revisions

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Importing Wikidata short description: Protein-coding gene in the species Homo sapiens (shortdescs-in-category)
 
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{{Short description|Protein-coding gene in the species Homo sapiens}}
{{PBB|geneid=6529}}
{{Infobox_gene}}


'''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]].<ref name="pmid8530094">{{cite journal | author = Huang F, Shi LJ, Heng HH, Fei J, Guo LH | title = Assignment of the human GABA transporter gene (GABATHG) locus to chromosome 3p24-p25 | journal = Genomics | volume = 29 | issue = 1 | pages = 302–4 | date = February 1996 | pmid = 8530094 | pmc = | doi = 10.1006/geno.1995.1253 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SLC6A1 solute carrier family 6 (neurotransmitter transporter, GABA), member 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6529| accessdate = }}</ref>
'''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.<ref name="pmid8530094">{{cite journal | vauthors = Huang F, Shi LJ, Heng HH, Fei J, Guo LH | title = Assignment of the human GABA transporter gene (GABATHG) locus to chromosome 3p24-p25 | journal = Genomics | volume = 29 | issue = 1 | pages = 302–304 | date = September 1995 | pmid = 8530094 | doi = 10.1006/geno.1995.1253 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SLC6A1 solute carrier family 6 (neurotransmitter transporter, GABA), member 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6529}}</ref><ref>{{cite journal | vauthors = Scimemi A | title = Structure, function, and plasticity of GABA transporters | journal = Frontiers in Cellular Neuroscience | volume = 8 | pages = 161 | date = 2014 | pmid = 24987330 | doi = 10.3389/fncel.2014.00161 | pmc = 4060055 | doi-access = free }}</ref> It mediates gamma-aminobutyric acid's translocation from the extracellular to intracellular spaces within brain tissue and the central nervous system as a whole.<ref name="Gonzalez-Burgo_2010">{{cite book | vauthors = Gonzalez-Burgos G | title = GABABReceptor Pharmacology - A Tribute to Norman Bowery | chapter = GABA transporter GAT1: a crucial determinant of GABAB receptor activation in cortical circuits? | series = Advances in Pharmacology | volume = 58 | pages = 175–204 | date = 2010 | pmid = 20655483 | doi = 10.1016/S1054-3589(10)58008-6 | isbn = 9780123786470 }}</ref><ref>{{cite journal | vauthors = Johannesen KM, Gardella E, Linnankivi T, Courage C, de Saint Martin A, Lehesjoki AE, Mignot C, Afenjar A, Lesca G, Abi-Warde MT, Chelly J, Piton A, Merritt JL, Rodan LH, Tan WH, Bird LM, Nespeca M, Gleeson JG, Yoo Y, Choi M, Chae JH, Czapansky-Beilman D, Reichert SC, Pendziwiat M, Verhoeven JS, Schelhaas HJ, Devinsky O, Christensen J, Specchio N, Trivisano M, Weber YG, Nava C, Keren B, Doummar D, Schaefer E, Hopkins S, Dubbs H, Shaw JE, Pisani L, Myers CT, Tang S, Tang S, Pal DK, Millichap JJ, Carvill GL, Helbig KL, Mecarelli O, Striano P, Helbig I, Rubboli G, Mefford HC, Møller RS | display-authors = 6 | title = Defining the phenotypic spectrum of SLC6A1 mutations | journal = Epilepsia | volume = 59 | issue = 2 | pages = 389–402 | date = February 2018 | pmid = 29315614 | pmc = 5912688 | doi = 10.1111/epi.13986 }}</ref>


== Structure ==
GAT1 is a 599 amino acid protein that consists of 12 transmembrane domains with an intracellular [[N-terminus]] and [[C-terminus]].<ref name="Zafar_2018">{{cite journal | vauthors = Zafar S, Jabeen I | title = Structure, Function, and Modulation of γ-Aminobutyric Acid Transporter 1 (GAT1) in Neurological Disorders: A Pharmacoinformatic Prospective | journal = Frontiers in Chemistry | volume = 6 | pages = 397 | date = 2018 | pmid = 30255012 | doi = 10.3389/fchem.2018.00397 | pmc = 6141625 | bibcode = 2018FrCh....6..397Z | doi-access = free }}</ref><ref name="Gonzalez-Burgo_2010" />
== Function ==
== 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).<ref name="pmid190776662">{{cite journal | vauthors = 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 | display-authors = 6 | title = Twenty-one-base-pair insertion polymorphism creates an enhancer element and potentiates SLC6A1 GABA transporter promoter activity | journal = Pharmacogenetics and Genomics | volume = 19 | issue = 1 | pages = 53–65 | date = January 2009 | pmid = 19077666 | pmc = 2791799 | doi = 10.1097/FPC.0b013e328318b21a }}</ref><ref>{{cite journal | vauthors = Madsen KK, Hansen GH, Danielsen EM, Schousboe A | title = The subcellular localization of GABA transporters and its implication for seizure management | journal = Neurochemical Research | volume = 40 | issue = 2 | pages = 410–419 | date = February 2015 | pmid = 25519681 | doi = 10.1007/s11064-014-1494-9 | s2cid = 19008879 }}</ref> GABA Transporter 1 uses energy from the dissipation of a Na<sup>+</sup> gradient, aided by the presence of a Cl<sup>−</sup> gradient, to translocate GABA across CNS neuronal membranes. The stoichiometry for GABA Transporter 1 is 2 Na<sup>+</sup>: 1 Cl<sup>−</sup>: 1 GABA.<ref>{{cite journal | vauthors = Jin XT, Galvan A, Wichmann T, Smith Y | title = Localization and Function of GABA Transporters GAT-1 and GAT-3 in the Basal Ganglia | journal = Frontiers in Systems Neuroscience | volume = 5 | pages = 63 | date = 28 July 2011 | pmid = 21847373 | pmc = 3148782 | doi = 10.3389/fnsys.2011.00063 | doi-access = free }}</ref> The presence of a Cl<sup>−</sup>/Cl<sup>−</sup> exchange is also proposed because the Cl<sup>−</sup> transported across the membrane does not affect the net charge.<ref>{{cite journal | vauthors = Loo DD, Eskandari S, Boorer KJ, Sarkar HK, Wright EM | title = Role of Cl- in electrogenic Na+-coupled cotransporters GAT1 and SGLT1 | language = English | journal = The Journal of Biological Chemistry | volume = 275 | issue = 48 | pages = 37414–37422 | date = December 2000 | pmid = 10973981 | doi = 10.1074/jbc.M007241200 | doi-access = free }}</ref> GABA is also the primary inhibitory neurotransmitter in the cerebral cortex and has the highest level of expression within it.<ref name="Conti_2004">{{cite journal | vauthors = Conti F, Minelli A, Melone M | title = GABA transporters in the mammalian cerebral cortex: localization, development and pathological implications | journal = Brain Research. Brain Research Reviews | volume = 45 | issue = 3 | pages = 196–212 | date = July 2004 | pmid = 15210304 | doi = 10.1016/j.brainresrev.2004.03.003 | s2cid = 19003675 }}</ref> The GABA affinity ([[Michaelis-Menten constant|K<sub>m</sub>]]) of the mouse isoform of GAT1 is 8 μM.<ref>{{cite journal | vauthors = Zhou Y, Danbolt NC | title = GABA and Glutamate Transporters in Brain | journal = Frontiers in Endocrinology | volume = 4 | pages = 165 | date = 2013 | pmid = 24273530 | doi = 10.3389/fendo.2013.00165 | pmc = 3822327 | doi-access = free }}</ref>
GAT1 a [[gamma-aminobutyric acid]] (GABA) transporter, which removes [[GABA]] from the synaptic cleft.<ref name="pmid19077666">{{cite journal | author = 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 | title = Twenty-one-base-pair insertion polymorphism creates an enhancer element and potentiates SLC6A1 GABA transporter promoter activity | journal = Pharmacogenet. Genomics | volume = 19 | issue = 1 | pages = 53–65 | date = January 2009 | pmid = 19077666 | pmc = 2791799 | doi = 10.1097/FPC.0b013e328318b21a | url = | issn = }}</ref>

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]].<ref name="Allen_2022">{{cite book | vauthors = Allen MJ, Sabir S, Sharma S | chapter = GABA Receptor |date=2022 | chapter-url = http://www.ncbi.nlm.nih.gov/books/NBK526124/ | title = StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30252380 |access-date=2022-04-11 }}</ref><ref name="Zafar_2018" /> 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.<ref name="Zafar_2018" />

=== Translocation cycle ===
Throughout the translocation cycle, GAT1 assumes three different conformations:

# '''Open-to-out.''' In this conformation, 2 extracellular Na<sup>+</sup> ions are co-transported into the neuron along with 1 GABA and 1 Cl<sup>−</sup> that bind to the empty transporter, thus making it fully loaded. In prokaryotes, it has been found that transport does not require Cl<sup>−</sup>. In mammals, the Cl<sup>−</sup> ion is required to offset the positive charge of the Na<sup>+</sup> in order to maintain the proper membrane potential.<ref name="Zafar_2018" />
# '''Occluded-out.''' Once fully loaded, this conformation prevents the release of ions/substrate into the cytoplasm or the extracellular space/synapse. The Na<sup>+</sup>, Cl<sup>−</sup>, and GABA are bound to the transporter until it changes conformation.<ref name="Zafar_2018" />
# '''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.<ref name="Zafar_2018" />

== 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]].<ref>{{cite journal | vauthors = Volk D, Austin M, Pierri J, Sampson A, Lewis D | title = GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons | journal = The American Journal of Psychiatry | volume = 158 | issue = 2 | pages = 256–265 | date = February 2001 | pmid = 11156808 | doi = 10.1176/appi.ajp.158.2.256 }}</ref><ref name="Hashimoto">{{cite journal | vauthors = Hashimoto T, Matsubara T, Lewis DA | title = [Schizophrenia and cortical GABA neurotransmission] | journal = Seishin Shinkeigaku Zasshi = Psychiatria et Neurologia Japonica | volume = 112 | issue = 5 | pages = 439–452 | date = 2010 | pmid = 20560363 }}</ref> 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..<ref name="Allen_2022" />

Imbalance in the GABAergic neurotransmission is involved in the pathophysiology of various neurological diseases such as epilepsy, Alzheimer's and stroke.<ref>{{cite journal | vauthors = Kickinger S, Hellsberg E, Frølund B, Schousboe A, Ecker GF, Wellendorph P | title = Structural and molecular aspects of betaine-GABA transporter 1 (BGT1) and its relation to brain function | journal = Neuropharmacology | volume = 161 | pages = 107644 | date = December 2019 | pmid = 31108110 | doi = 10.1016/j.neuropharm.2019.05.021 | series = Neurotransmitter Transporters | s2cid = 156055973 }}</ref>

A study on genetic absence epilepsy rats from Strasbourg ([[Genetic Absence Epilepsy Rat|GAERS]]) found that poor GABA uptake by GAT1 caused an increase in tonic current of GABA<sub>A</sub>. In the two most understood forms of absence epilepsy, synaptic GABA<sub>A</sub> 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.<ref>{{cite journal | vauthors = Cope DW, Di Giovanni G, Fyson SJ, Orbán G, Errington AC, Lorincz ML, Gould TM, Carter DA, Crunelli V | display-authors = 6 | title = Enhanced tonic GABAA inhibition in typical absence epilepsy | journal = Nature Medicine | volume = 15 | issue = 12 | pages = 1392–1398 | date = December 2009 | pmid = 19966779 | doi = 10.1038/nm.2058 | pmc = 2824149 }}</ref>

Glutamate and GABA have also been found to interact within the [[Solitary nucleus|nucleus tractus solitarii]] (NTS), [[Paraventricular nucleus of hypothalamus|paraventricular nucleus]] (PVN), and [[rostral ventrolateral medulla]] (RVLM) of the brain to modulate blood pressure.<ref>{{cite journal | vauthors = Dupont AG, Légat L | title = GABA is a mediator of brain AT<sub>1</sub> and AT<sub>2</sub> receptor-mediated blood pressure responses | journal = Hypertension Research | volume = 43 | issue = 10 | pages = 995–1005 | date = October 2020 | pmid = 32451494 | doi = 10.1038/s41440-020-0470-9 | s2cid = 218864718 }}</ref>


== Interactions ==
== Interactions ==


SLC6A1 has been shown to [[Protein-protein interaction|interact]] with [[STX1A]].<ref name = pmid9698305>{{cite journal | author = Beckman ML, Bernstein EM, Quick MW | title = Protein kinase C regulates the interaction between a GABA transporter and syntaxin 1A | journal = J. Neurosci. | volume = 18 | issue = 16 | pages = 6103-12 | date = August 1998 | pmid = 9698305 | doi = }}</ref><ref name = pmid11960023>{{cite journal | author = Quick MW | title = Substrates regulate gamma-aminobutyric acid transporters in a syntaxin 1A-dependent manner | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 99 | issue = 8 | pages = 5686-91 | date = April 2002 | pmid = 11960023 | pmc = 122832 | doi = 10.1073/pnas.082712899 }}</ref><ref name = pmid11017172>{{cite journal | author = Deken SL, Beckman ML, Boos L, Quick MW | title = Transport rates of GABA transporters: regulation by the N-terminal domain and syntaxin 1A | journal = Nat. Neurosci. | volume = 3 | issue = 10 | pages = 998-1003 | date = October 2000 | pmid = 11017172 | doi = 10.1038/79939 }}</ref>
SLC6A1 has been shown to [[Protein-protein interaction|interact]] with [[STX1A]].<ref name = pmid9698305>{{cite journal | vauthors = Beckman ML, Bernstein EM, Quick MW | title = Protein kinase C regulates the interaction between a GABA transporter and syntaxin 1A | journal = The Journal of Neuroscience | volume = 18 | issue = 16 | pages = 6103–6112 | date = August 1998 | pmid = 9698305 | pmc = 6793212 | doi = 10.1523/JNEUROSCI.18-16-06103.1998 | doi-access = free }}</ref><ref name = pmid11960023>{{cite journal | vauthors = Quick MW | title = Substrates regulate gamma-aminobutyric acid transporters in a syntaxin 1A-dependent manner | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 8 | pages = 5686–5691 | date = April 2002 | pmid = 11960023 | pmc = 122832 | doi = 10.1073/pnas.082712899 | doi-access = free | bibcode = 2002PNAS...99.5686Q }}</ref><ref name = pmid11017172>{{cite journal | vauthors = Deken SL, Beckman ML, Boos L, Quick MW | title = Transport rates of GABA transporters: regulation by the N-terminal domain and syntaxin 1A | journal = Nature Neuroscience | volume = 3 | issue = 10 | pages = 998–1003 | date = October 2000 | pmid = 11017172 | doi = 10.1038/79939 | s2cid = 11312913 }}</ref>


== See also ==
== See also ==
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* [[GABA transporter type 2|GABA transporter 2]]
* [[GABA transporter type 2|GABA transporter 2]]
* [[GABA transporter type 3|GABA transporter 3]]
* [[GABA transporter type 3|GABA transporter 3]]
* [[SLC6A1 epileptic encephalopathy]]


== References ==
== References ==
{{Reflist|2}}
{{Reflist|30em}}


== Further reading ==
== Further reading ==
{{refbegin | 2}}
{{refbegin|30em}}
*{{cite journal | author = Nelson H, Mandiyan S, Nelson N | title = Cloning of the human brain GABA transporter. | journal = FEBS Lett. | volume = 269 | issue = 1 | pages = 181–4 | year = 1990 | pmid = 2387399 | doi = 10.1016/0014-5793(90)81149-I }}
* {{cite journal | vauthors = Nelson H, Mandiyan S, Nelson N | title = Cloning of the human brain GABA transporter | journal = FEBS Letters | volume = 269 | issue = 1 | pages = 181–184 | date = August 1990 | pmid = 2387399 | doi = 10.1016/0014-5793(90)81149-I | s2cid = 34636220 | doi-access = free }}
*{{cite journal | author = Bennett ER, Kanner BI | title = The membrane topology of GAT-1, a (Na+ + Cl-)-coupled gamma-aminobutyric acid transporter from rat brain. | journal = J. Biol. Chem. | volume = 272 | issue = 2 | pages = 1203–10 | year = 1997 | pmid = 8995422 | doi = 10.1074/jbc.272.2.1203 }}
* {{cite journal | vauthors = Bennett ER, Kanner BI | title = The membrane topology of GAT-1, a (Na+ + Cl-)-coupled gamma-aminobutyric acid transporter from rat brain | journal = The Journal of Biological Chemistry | volume = 272 | issue = 2 | pages = 1203–1210 | date = January 1997 | pmid = 8995422 | doi = 10.1074/jbc.272.2.1203 | doi-access = free }}
*{{cite journal | author = Bismuth Y, Kavanaugh MP, Kanner BI | title = Tyrosine 140 of the gamma-aminobutyric acid transporter GAT-1 plays a critical role in neurotransmitter recognition. | journal = J. Biol. Chem. | volume = 272 | issue = 26 | pages = 16096–102 | year = 1997 | pmid = 9195904 | doi = 10.1074/jbc.272.26.16096 }}
* {{cite journal | vauthors = Bismuth Y, Kavanaugh MP, Kanner BI | title = Tyrosine 140 of the gamma-aminobutyric acid transporter GAT-1 plays a critical role in neurotransmitter recognition | journal = The Journal of Biological Chemistry | volume = 272 | issue = 26 | pages = 16096–16102 | date = June 1997 | pmid = 9195904 | doi = 10.1074/jbc.272.26.16096 | doi-access = free }}
*{{cite journal | author = DeFelipe J, González-Albo MC | title = Chandelier cell axons are immunoreactive for GAT-1 in the human neocortex. | journal = NeuroReport | volume = 9 | issue = 3 | pages = 467–70 | year = 1998 | pmid = 9512391 | doi = 10.1097/00001756-199802160-00020 }}
* {{cite journal | vauthors = DeFelipe J, González-Albo MC | title = Chandelier cell axons are immunoreactive for GAT-1 in the human neocortex | journal = NeuroReport | volume = 9 | issue = 3 | pages = 467–470 | date = February 1998 | pmid = 9512391 | doi = 10.1097/00001756-199802160-00020 | s2cid = 27446580 }}
*{{cite journal | author = Conti F, Melone M, De Biasi S, Minelli A, Brecha NC, Ducati A | title = 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. | journal = J. Comp. Neurol. | volume = 396 | issue = 1 | pages = 51–63 | year = 1998 | pmid = 9623887 | doi = 10.1002/(SICI)1096-9861(19980622)396:1<51::AID-CNE5>3.0.CO;2-H }}
* {{cite journal | vauthors = Conti F, Melone M, De Biasi S, Minelli A, Brecha NC, Ducati A | title = 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 | journal = The Journal of Comparative Neurology | volume = 396 | issue = 1 | pages = 51–63 | date = June 1998 | pmid = 9623887 | doi = 10.1002/(SICI)1096-9861(19980622)396:1<51::AID-CNE5>3.0.CO;2-H | s2cid = 33438310 }}
*{{cite journal | author = Beckman ML, Bernstein EM, Quick MW | title = Protein kinase C regulates the interaction between a GABA transporter and syntaxin 1A. | journal = J. Neurosci. | volume = 18 | issue = 16 | pages = 6103–12 | year = 1998 | pmid = 9698305 | doi = }}
* {{cite journal | vauthors = Augood SJ, Waldvogel HJ, Münkle MC, Faull RL, Emson PC | title = Localization of calcium-binding proteins and GABA transporter (GAT-1) messenger RNA in the human subthalamic nucleus | journal = Neuroscience | volume = 88 | issue = 2 | pages = 521–534 | date = January 1999 | pmid = 10197772 | doi = 10.1016/S0306-4522(98)00226-7 | s2cid = 2514970 }}
*{{cite journal | author = Augood SJ, Waldvogel HJ, Münkle MC, Faull RL, Emson PC | title = Localization of calcium-binding proteins and GABA transporter (GAT-1) messenger RNA in the human subthalamic nucleus. | journal = Neuroscience | volume = 88 | issue = 2 | pages = 521–34 | year = 1999 | pmid = 10197772 | doi = 10.1016/S0306-4522(98)00226-7 }}
* {{cite journal | vauthors = Ong WY, Yeo TT, Balcar VJ, Garey LJ | title = A light and electron microscopic study of GAT-1-positive cells in the cerebral cortex of man and monkey | journal = Journal of Neurocytology | volume = 27 | issue = 10 | pages = 719–730 | date = October 1998 | pmid = 10640187 | doi = 10.1023/A:1006946717065 | s2cid = 39552099 }}
*{{cite journal | author = Ong WY, Yeo TT, Balcar VJ, Garey LJ | title = A light and electron microscopic study of GAT-1-positive cells in the cerebral cortex of man and monkey. | journal = J. Neurocytol. | volume = 27 | issue = 10 | pages = 719–30 | year = 2000 | pmid = 10640187 | doi = 10.1023/A:1006946717065 }}
* {{cite journal | vauthors = Whitworth TL, Quick MW | title = Substrate-induced regulation of gamma-aminobutyric acid transporter trafficking requires tyrosine phosphorylation | journal = The Journal of Biological Chemistry | volume = 276 | issue = 46 | pages = 42932–42937 | date = November 2001 | pmid = 11555659 | doi = 10.1074/jbc.M107638200 | doi-access = free }}
*{{cite journal | author = Deken SL, Beckman ML, Boos L, Quick MW | title = Transport rates of GABA transporters: regulation by the N-terminal domain and syntaxin 1A. | journal = Nat. Neurosci. | volume = 3 | issue = 10 | pages = 998–1003 | year = 2000 | pmid = 11017172 | doi = 10.1038/79939 }}
* {{cite journal | vauthors = Hachiya Y, Takashima S | title = Development of GABAergic neurons and their transporter in human temporal cortex | journal = Pediatric Neurology | volume = 25 | issue = 5 | pages = 390–396 | date = November 2001 | pmid = 11744314 | doi = 10.1016/S0887-8994(01)00348-4 }}
*{{cite journal | author = Whitworth TL, Quick MW | title = Substrate-induced regulation of gamma-aminobutyric acid transporter trafficking requires tyrosine phosphorylation. | journal = J. Biol. Chem. | volume = 276 | issue = 46 | pages = 42932–7 | year = 2001 | pmid = 11555659 | doi = 10.1074/jbc.M107638200 }}
* {{cite journal | vauthors = Kanner BI | title = Transmembrane domain I of the gamma-aminobutyric acid transporter GAT-1 plays a crucial role in the transition between cation leak and transport modes | journal = The Journal of Biological Chemistry | volume = 278 | issue = 6 | pages = 3705–3712 | date = February 2003 | pmid = 12446715 | doi = 10.1074/jbc.M210525200 | doi-access = free }}
*{{cite journal | author = Hachiya Y, Takashima S | title = Development of GABAergic neurons and their transporter in human temporal cortex. | journal = Pediatr. Neurol. | volume = 25 | issue = 5 | pages = 390–6 | year = 2002 | pmid = 11744314 | doi = 10.1016/S0887-8994(01)00348-4 }}
* {{cite journal | vauthors = Zomot E, Kanner BI | title = 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 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 44 | pages = 42950–42958 | date = October 2003 | pmid = 12925537 | doi = 10.1074/jbc.M209307200 | doi-access = free }}
*{{cite journal | author = Quick MW | title = Substrates regulate gamma-aminobutyric acid transporters in a syntaxin 1A-dependent manner. | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 99 | issue = 8 | pages = 5686–91 | year = 2002 | pmid = 11960023 | pmc = 122832 | doi = 10.1073/pnas.082712899 }}
* {{cite journal | vauthors = Zhou Y, Bennett ER, Kanner BI | title = The aqueous accessibility in the external half of transmembrane domain I of the GABA transporter GAT-1 Is modulated by its ligands | journal = The Journal of Biological Chemistry | volume = 279 | issue = 14 | pages = 13800–13808 | date = April 2004 | pmid = 14744863 | doi = 10.1074/jbc.M311579200 | doi-access = free }}
*{{cite journal | author = Kanner BI | title = Transmembrane domain I of the gamma-aminobutyric acid transporter GAT-1 plays a crucial role in the transition between cation leak and transport modes. | journal = J. Biol. Chem. | volume = 278 | issue = 6 | pages = 3705–12 | year = 2003 | pmid = 12446715 | doi = 10.1074/jbc.M210525200 }}
* {{cite journal | vauthors = Hu JH, Ma YH, Jiang J, Yang N, Duan SH, Jiang ZH, Mei ZT, Fei J, Guo LH | display-authors = 6 | title = Cognitive impairment in mice over-expressing gamma-aminobutyric acid transporter 1 (GAT1) | journal = NeuroReport | volume = 15 | issue = 1 | pages = 9–12 | date = January 2004 | pmid = 15106822 | doi = 10.1097/00001756-200401190-00003 | s2cid = 6407617 }}
*{{cite journal | author = Zomot E, Kanner BI | title = 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. | journal = J. Biol. Chem. | volume = 278 | issue = 44 | pages = 42950–8 | year = 2003 | pmid = 12925537 | doi = 10.1074/jbc.M209307200 }}
* {{cite journal | vauthors = Korkhov VM, Farhan H, Freissmuth M, Sitte HH | title = Oligomerization of the {gamma}-aminobutyric acid transporter-1 is driven by an interplay of polar and hydrophobic interactions in transmembrane helix II | journal = The Journal of Biological Chemistry | volume = 279 | issue = 53 | pages = 55728–55736 | date = December 2004 | pmid = 15496410 | doi = 10.1074/jbc.M409449200 | doi-access = free }}
*{{cite journal | author = Zhou Y, Bennett ER, Kanner BI | title = The aqueous accessibility in the external half of transmembrane domain I of the GABA transporter GAT-1 Is modulated by its ligands. | journal = J. Biol. Chem. | volume = 279 | issue = 14 | pages = 13800–8 | year = 2004 | pmid = 14744863 | doi = 10.1074/jbc.M311579200 }}
*{{cite journal | author = Hu JH, Ma YH, Jiang J, Yang N, Duan SH, Jiang ZH, Mei ZT, Fei J, Guo LH | title = Cognitive impairment in mice over-expressing gamma-aminobutyric acid transporter 1 (GAT1). | journal = NeuroReport | volume = 15 | issue = 1 | pages = 9–12 | year = 2004 | pmid = 15106822 | doi = 10.1097/00001756-200401190-00003 }}
*{{cite journal | author = Korkhov VM, Farhan H, Freissmuth M, Sitte HH | title = Oligomerization of the {gamma}-aminobutyric acid transporter-1 is driven by an interplay of polar and hydrophobic interactions in transmembrane helix II. | journal = J. Biol. Chem. | volume = 279 | issue = 53 | pages = 55728–36 | year = 2005 | pmid = 15496410 | doi = 10.1074/jbc.M409449200 }}
{{refend}}
{{refend}}


{{NLM content}}
{{NLM content}}

{{GABAergics}}
{{Membrane transport proteins}}
{{Membrane transport proteins}}
{{Neurotransmitter transporters}}
{{Neurotransmitter transporters}}
{{GABA metabolism and transport modulators}}


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

[[Category:Neurotransmitter transporters]]
[[Category:Neurotransmitter transporters]]



{{membrane-protein-stub}}
{{membrane-protein-stub}}

Latest revision as of 22:11, 3 March 2023

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[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− gradient, to translocate GABA across CNS neuronal membranes. The stoichiometry for GABA Transporter 1 is 2 Na+: 1 Cl−: 1 GABA.[13] The presence of a Cl−/Cl− exchange is also proposed because the Cl− 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 μM.[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:

  1. Open-to-out. In this conformation, 2 extracellular Na+ ions are co-transported into the neuron along with 1 GABA and 1 Cl− that bind to the empty transporter, thus making it fully loaded. In prokaryotes, it has been found that transport does not require Cl−. In mammals, the Cl− ion is required to offset the positive charge of the Na+ in order to maintain the proper membrane potential.[10]
  2. Occluded-out. Once fully loaded, this conformation prevents the release of ions/substrate into the cytoplasm or the extracellular space/synapse. The Na+, Cl−, and GABA are bound to the transporter until it changes conformation.[10]
  3. 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]

  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): 302–304. doi:10.1006/geno.1995.1253. PMID 8530094.
  6. ^ "Entrez Gene: SLC6A1 solute carrier family 6 (neurotransmitter transporter, GABA), member 1".
  7. ^ Scimemi A (2014). "Structure, function, and plasticity of GABA transporters". Frontiers in Cellular Neuroscience. 8: 161. doi:10.3389/fncel.2014.00161. PMC 4060055. PMID 24987330.
  8. ^ 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. 58. pp. 175–204. doi:10.1016/S1054-3589(10)58008-6. ISBN 9780123786470. PMID 20655483.
  9. ^ Johannesen KM, Gardella E, Linnankivi T, Courage C, de Saint Martin A, Lehesjoki AE, et al. (February 2018). "Defining the phenotypic spectrum of SLC6A1 mutations". Epilepsia. 59 (2): 389–402. doi:10.1111/epi.13986. PMC 5912688. PMID 29315614.
  10. ^ a b c d e f Zafar S, Jabeen I (2018). "Structure, Function, and Modulation of γ-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 6141625. PMID 30255012.
  11. ^ Hirunsatit R, George ED, Lipska BK, Elwafi HM, Sander L, Yrigollen CM, et al. (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.
  12. ^ 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): 410–419. doi:10.1007/s11064-014-1494-9. PMID 25519681. S2CID 19008879.
  13. ^ 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.
  14. ^ 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): 37414–37422. doi:10.1074/jbc.M007241200. PMID 10973981.
  15. ^ 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): 196–212. doi:10.1016/j.brainresrev.2004.03.003. PMID 15210304. S2CID 19003675.
  16. ^ Zhou Y, Danbolt NC (2013). "GABA and Glutamate Transporters in Brain". Frontiers in Endocrinology. 4: 165. doi:10.3389/fendo.2013.00165. PMC 3822327. PMID 24273530.
  17. ^ a b Allen MJ, Sabir S, Sharma S (2022). "GABA Receptor". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 30252380. Retrieved 2022-04-11.
  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): 256–265. 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): 439–452. PMID 20560363.
  20. ^ Kickinger S, Hellsberg E, Frølund 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 31108110. S2CID 156055973.
  21. ^ Cope DW, Di Giovanni G, Fyson SJ, Orbán G, Errington AC, Lorincz ML, et al. (December 2009). "Enhanced tonic GABAA inhibition in typical absence epilepsy". Nature Medicine. 15 (12): 1392–1398. doi:10.1038/nm.2058. PMC 2824149. PMID 19966779.
  22. ^ Dupont AG, Légat L (October 2020). "GABA is a mediator of brain AT1 and AT2 receptor-mediated blood pressure responses". Hypertension Research. 43 (10): 995–1005. doi:10.1038/s41440-020-0470-9. PMID 32451494. S2CID 218864718.
  23. ^ 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): 6103–6112. doi:10.1523/JNEUROSCI.18-16-06103.1998. PMC 6793212. PMID 9698305.
  24. ^ 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): 5686–5691. Bibcode:2002PNAS...99.5686Q. doi:10.1073/pnas.082712899. PMC 122832. PMID 11960023.
  25. ^ 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[edit]

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

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