GABA transporter type 1

GAT1 is a 599 amino acid protein that consists of 12 transmembrane domains with an intracellular N-terminus and C-terminus.{{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 }}

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).{{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 }}{{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 }} 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.{{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 }} The presence of a Cl⁻/Cl⁻ exchange is also proposed because the Cl⁻ transported across the membrane does not affect the net charge.{{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 }} GABA is also the primary inhibitory neurotransmitter in the cerebral cortex and has the highest level of expression within it.{{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 }} The GABA affinity (K_m) of the mouse isoform of GAT1 is 8 μM.{{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 }}

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.{{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 }} 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.

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.
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.
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.

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.{{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 }}{{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 }} 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..

Imbalance in the GABAergic neurotransmission is involved in the pathophysiology of various neurological diseases such as epilepsy, Alzheimer's and stroke.{{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 }}

A study on genetic absence epilepsy rats from Strasbourg (GAERS) found that poor GABA uptake by GAT1 caused an increase in tonic current of GABA_A. In the two most understood forms of absence epilepsy, synaptic GABA_A 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.{{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 }}

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.{{cite journal | vauthors = Dupont AG, Légat L | title = GABA is a mediator of brain AT₁ and AT₂ 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 }}

SLC6A1 has been shown to interact with STX1A.{{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 }}{{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 }}{{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 }}

• Solute carrier family
• GABA transporter 2
• GABA transporter 3
• SLC6A1 epileptic encephalopathy

{{Reflist|30em}}

{{refbegin|30em}}

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{{NLM content}}

{{Membrane transport proteins}}

{{Neurotransmitter transporters}}

{{GABA metabolism and transport modulators}}

Category:Solute carrier family

Category:Neurotransmitter transporters