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== Function == === Neurotransmitter === Two general classes of [[GABA receptor]] are known:<ref>{{Cite book |last1=Marescaux |first1=C. |url=https://books.google.com/books?id=YggrBgAAQBAJ&pg=PT80 |title=Generalized Non-Convulsive Epilepsy: Focus on GABA-B Receptors |last2=Vergnes |first2=M. |last3=Bernasconi |first3=R. |date=2013-03-08 |publisher=Springer Science & Business Media |isbn=978-3-7091-9206-1 |language=en}}</ref> * [[GABAA receptor|GABA<sub>A</sub>]] in which the receptor is part of a [[ligand-gated ion channel]] complex<ref name="elifesciences.org">{{Cite journal |last1=Phulera |first1=Swastik |last2=Zhu |first2=Hongtao |last3=Yu |first3=Jie |last4=Claxton |first4=Derek P. |last5=Yoder |first5=Nate |last6=Yoshioka |first6=Craig |last7=Gouaux |first7=Eric |date=2018-07-25 |title=Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2S tri-heteromeric GABA<sub>A</sub> receptor in complex with GABA |journal=eLife |language=en |volume=7 |pages=e39383 |doi=10.7554/eLife.39383 |doi-access=free |issn=2050-084X |pmc=6086659 |pmid=30044221}}</ref> * [[GABAB receptor|GABA<sub>B</sub>]] [[metabotropic receptor]]s, which are [[G protein-coupled receptor]]s that open or close ion channels via intermediaries ([[G protein]]s) [[File:Release, Reuptake, and Metabolism Cycle of GABA.png|class=skin-invert-image|alt=|thumb|500x500px|Release, reuptake, and metabolism cycle of GABA]] Neurons that produce GABA as their output are called [[GABAergic]] neurons, and have chiefly inhibitory action at receptors in the adult vertebrate. [[Medium spiny neuron|Medium spiny cells]] are a typical example of inhibitory [[central nervous system]] GABAergic cells. In contrast, GABA exhibits both excitatory and inhibitory actions in [[insect]]s, mediating [[muscle]] activation at synapses between [[nerve]]s and muscle cells, and also the stimulation of certain [[gland]]s.<ref name="pmid8389005">{{cite journal |vauthors= Ffrench-Constant RH, Rocheleau TA, Steichen JC, Chalmers AE |title= A point mutation in a ''Drosophila'' GABA receptor confers insecticide resistance |journal= Nature |volume= 363 |issue= 6428 |pages= 449–51 |date= June 1993 |pmid= 8389005 |doi= 10.1038/363449a0 |bibcode= 1993Natur.363..449F|s2cid= 4334499 }}</ref> In mammals, some GABAergic neurons, such as [[chandelier cell]]s, are also able to excite their glutamatergic counterparts.<ref name="pmid16410524">{{cite journal |vauthors= Szabadics J, Varga C, Molnár G, Oláh S, Barzó P, Tamás G |title= Excitatory effect of GABAergic axo-axonic cells in cortical microcircuits |journal= Science |volume= 311 |issue= 5758 |pages= 233–235 |date= January 2006 |pmid= 16410524 |doi= 10.1126/science.1121325 |bibcode= 2006Sci...311..233S|s2cid= 40744562 }}</ref> In addition to fast-acting phasic inhibition, small amounts of extracellular GABA can induce slow timescale tonic inhibition on neurons.<ref name="Koh Kwak Cheong Lee 2023">{{cite journal |last1=Koh |first1=Wuhyun |last2=Kwak |first2=Hankyul |last3=Cheong |first3=Eunji |last4=Lee |first4=C. Justin |date=2023-07-26 |title=GABA tone regulation and its cognitive functions in the brain |journal=Nature Reviews Neuroscience |volume=24 |issue=9 |pages=523–539 |doi=10.1038/s41583-023-00724-7 |pmid=37495761 |s2cid=260201740 |issn=1471-003X}}</ref> [[GABAA receptor|GABA<sub>A</sub> receptors]] are ligand-activated chloride channels: when activated by GABA, they allow the flow of [[chloride]] ions across the membrane of the cell.<ref name="elifesciences.org"/> Whether this chloride flow is depolarizing (makes the voltage across the cell's membrane less negative), shunting (has no effect on the cell's membrane potential), or inhibitory/hyperpolarizing (makes the cell's membrane more negative) depends on the direction of the flow of chloride. When net chloride flows out of the cell, GABA is depolarising; when chloride flows into the cell, GABA is inhibitory or hyperpolarizing. When the net flow of chloride is close to zero, the action of GABA is shunting. [[Shunting inhibition]] has no direct effect on the membrane potential of the cell; however, it reduces the effect of any coincident synaptic input by reducing the [[electrical resistance and conductance|electrical resistance]] of the cell's membrane. Shunting inhibition can "override" the excitatory effect of depolarising GABA, resulting in overall inhibition even if the membrane potential becomes less negative. It was thought that a developmental switch in the molecular machinery controlling the concentration of chloride inside the cell changes the functional role of GABA between [[neonatal]] and adult stages. As the brain develops into adulthood, GABA's role changes from excitatory to inhibitory.<ref name="pmid18500393">{{cite journal |vauthors= Li K, Xu E |title= The role and the mechanism of γ-aminobutyric acid during central nervous system development |journal= Neurosci Bull |volume= 24 |issue= 3 |pages= 195–200 |date= June 2008 |pmid= 18500393 |pmc= 5552538 |doi= 10.1007/s12264-008-0109-3}}</ref> === Brain development === GABA is an inhibitory transmitter in the mature brain; its actions were thought to be primarily excitatory in the developing brain.<ref name="pmid18500393"/><ref name="pmid17928584">{{cite journal |vauthors= Ben-Ari Y, Gaiarsa JL, Tyzio R, Khazipov R |title= GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations |journal= Physiol. Rev. |volume= 87 |issue= 4 |pages= 1215–1284 |date= October 2007 |pmid= 17928584 |doi= 10.1152/physrev.00017.2006}}</ref> The gradient of chloride was reported to be reversed in immature neurons, with its reversal potential higher than the resting membrane potential of the cell; activation of a GABA-A receptor thus leads to efflux of Cl<sup>−</sup> ions from the cell (that is, a depolarizing current). The differential gradient of chloride in immature neurons was shown to be primarily due to the higher concentration of NKCC1 co-transporters relative to KCC2 co-transporters in immature cells. GABAergic interneurons mature faster in the hippocampus and the GABA machinery appears earlier than glutamatergic transmission. Thus, GABA is considered the major excitatory neurotransmitter in many regions of the brain before the [[neural development|maturation]] of [[glutamate]]rgic synapses.<ref>{{Cite book|last1=Schousboe|first1=Arne|url=https://books.google.com/books?id=rrKVDQAAQBAJ&pg=PA311|title=The Glutamate/GABA-Glutamine Cycle: Amino Acid Neurotransmitter Homeostasis|last2=Sonnewald|first2=Ursula|date=2016-11-25|publisher=Springer|isbn=978-3-319-45096-4|language=en}}</ref> In the developmental stages preceding the formation of synaptic contacts, GABA is synthesized by neurons and acts both as an [[autocrine]] (acting on the same cell) and [[paracrine]] (acting on nearby cells) signalling mediator.<ref name="isbn0-87893-697-1">{{cite book |veditors=Purves D, Fitzpatrick D, Hall WC, Augustine GJ, Lamantia AS |title= Neuroscience |edition= 4th |publisher= Sinauer |location= Sunderland, Mass |year= 2007 |pages= [https://archive.org/details/neuroscienceissu00purv/page/n160 135], box 6D |isbn= 978-0-87893-697-7 |url=https://archive.org/details/neuroscienceissu00purv|url-access=limited }}</ref><ref name="pmid16512345">{{cite book |vauthors= Jelitai M, Madarasz E |title= GABA in Autism and Related Disorders |chapter= The role of GABA in the early neuronal development |volume= 71 |pages= 27–62 |year= 2005 |pmid= 16512345 |doi= 10.1016/S0074-7742(05)71002-3 |chapter-url=https://books.google.com/books?id=IUb5ewXY09YC&pg=PA27 |isbn= 9780123668721 |series= International Review of Neurobiology}}</ref> The [[ganglionic eminence]]s also contribute greatly to building up the GABAergic cortical cell population.<ref name="pmid11715055">{{cite journal |vauthors= Marín O, Rubenstein JL |title= A long, remarkable journey: tangential migration in the telencephalon |journal= Nat. Rev. Neurosci. |volume= 2 |issue= 11 |pages= 780–90 |date= November 2001 |pmid= 11715055 |doi= 10.1038/35097509|s2cid= 5604192 }}</ref> GABA regulates the proliferation of neural [[progenitor cell]]s,<ref name="pmid8845153">{{cite journal |vauthors= LoTurco JJ, Owens DF, Heath MJ, Davis MB, Kriegstein AR |title= GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis |journal= Neuron |volume= 15 |issue= 6 |pages= 1287–1298 |date= December 1995 |pmid= 8845153 |doi= 10.1016/0896-6273(95)90008-X|s2cid= 1366263 |doi-access= free }}</ref><ref name="pmid10908617">{{cite journal |vauthors= Haydar TF, Wang F, Schwartz ML, Rakic P |title= Differential modulation of proliferation in the neocortical ventricular and subventricular zones |journal= J. Neurosci. |volume= 20 |issue= 15 |pages= 5764–74 |date= August 2000 |pmid= 10908617 |pmc= 3823557 |doi= 10.1523/JNEUROSCI.20-15-05764.2000}}</ref> the migration<ref name="pmid9698329">{{cite journal |vauthors= Behar TN, Schaffner AE, Scott CA, O'Connell C, Barker JL |title= Differential response of cortical plate and ventricular zone cells to GABA as a migration stimulus |journal= J. Neurosci. |volume= 18 |issue= 16 |pages= 6378–87 |date= August 1998 |pmid= 9698329 |pmc= 6793175 |doi= 10.1523/JNEUROSCI.18-16-06378.1998}}</ref> and [[cellular differentiation|differentiation]]<ref name="pmid11371348">{{cite journal |vauthors= Ganguly K, Schinder AF, Wong ST, Poo M |title= GABA itself promotes the developmental switch of neuronal GABAergic responses from excitation to inhibition |journal= Cell |volume= 105 |issue= 4 |pages= 521–32 |date= May 2001 |pmid= 11371348 |doi= 10.1016/S0092-8674(01)00341-5|s2cid= 8615968 |doi-access= free }}</ref><ref name="pmid8390627">{{cite journal |vauthors= Barbin G, Pollard H, Gaïarsa JL, Ben-Ari Y |title= Involvement of GABAA receptors in the outgrowth of cultured hippocampal neurons |journal= Neurosci. Lett. |volume= 152 |issue= 1–2 |pages= 150–154 |date= April 1993 |pmid= 8390627 |doi= 10.1016/0304-3940(93)90505-F|s2cid= 30672030 }}</ref> the elongation of [[neurite]]s<ref name="pmid11264309">{{cite journal |vauthors= Maric D, Liu QY, Maric I, Chaudry S, Chang YH, Smith SV, Sieghart W, Fritschy JM, Barker JL |title= GABA expression dominates neuronal lineage progression in the embryonic rat neocortex and facilitates neurite outgrowth via GABA(A) autoreceptor/Cl<sup>−</sup> channels |journal= J. Neurosci. |volume= 21 |issue= 7 |pages= 2343–60 |date= April 2001 |pmid= 11264309 |pmc= 6762405 |doi= 10.1523/JNEUROSCI.21-07-02343.2001}}</ref> and the formation of synapses.<ref name="pmid12209121">{{cite journal |vauthors= Ben-Ari Y |title= Excitatory actions of gaba during development: the nature of the nurture |journal= Nat. Rev. Neurosci. |volume= 3 |issue= 9 |pages= 728–739 |date= September 2002 |pmid= 12209121 |doi= 10.1038/nrn920|s2cid= 8116740 |url=http://www.hal.inserm.fr/inserm-00484852 |url-access= subscription }}</ref> GABA also regulates the growth of [[embryonic stem cell|embryonic]] and [[neural stem cell]]s. GABA can influence the development of neural progenitor cells via [[brain-derived neurotrophic factor]] (BDNF) expression.<ref name="pmid12163549">{{cite journal |vauthors= Obrietan K, Gao XB, Van Den Pol AN |title= Excitatory actions of GABA increase BDNF expression via a MAPK-CREB-dependent mechanism—a positive feedback circuit in developing neurons |journal= J. Neurophysiol. |volume= 88 |issue= 2 |pages= 1005–15 |date= August 2002 |pmid= 12163549 |doi= 10.1152/jn.2002.88.2.1005}}</ref> GABA activates the [[GABAA receptor|GABA<sub>A</sub> receptor]], causing cell cycle arrest in the S-phase, limiting growth.<ref name="pmid18852839">{{cite journal |vauthors= Wang DD, Kriegstein AR, Ben-Ari Y |title= GABA regulates stem cell proliferation before nervous system formation |journal= Epilepsy Curr |volume= 8 |issue= 5 |pages= 137–9 |year= 2008 |pmid= 18852839 |pmc= 2566617 |doi= 10.1111/j.1535-7511.2008.00270.x}}</ref> === Beyond the nervous system === [[File:Autoradiography of a brain slice from an embryonal rat - PMID19190758 PLoS 0004371.png|thumb|240px|mRNA expression of the embryonic variant of the GABA-producing enzyme [[GAD67]] in a coronal brain section of a one-day-old [[Laboratory rat#Wistar rat|Wistar rat]], with the highest expression in [[subventricular zone]] (svz)<ref name="pmid19190758">{{cite journal |vauthors=Popp A, Urbach A, Witte OW, Frahm C |title=Adult and embryonic GAD transcripts are spatiotemporally regulated during postnatal development in the rat brain |journal=[[PLoS ONE]] |volume=4 |issue=2 |pages=e4371 |year=2009 |pmid=19190758 |pmc=2629816|doi=10.1371/journal.pone.0004371 |editor1-last=Reh |editor1-first=Thomas A.|bibcode= 2009PLoSO...4.4371P|doi-access=free }}</ref>]] Besides the nervous system, GABA is also produced at relatively high levels in the [[insulin]]-producing [[beta cell]]s (β-cells) of the [[pancreas]]. The β-cells secrete GABA along with insulin and the GABA binds to GABA receptors on the neighboring [[pancreatic islets|islet]] [[alpha cell]]s (α-cells) and inhibits them from secreting [[glucagon]] (which would counteract insulin's effects).<ref name="pmid2550826">{{cite journal |vauthors=Rorsman P, Berggren PO, Bokvist K, Ericson H, Möhler H, Ostenson CG, Smith PA |title=Glucose-inhibition of glucagon secretion involves activation of GABA<sub>A</sub>-receptor chloride channels |journal=Nature |volume=341 |issue=6239 |pages=233–6 |year=1989 |pmid=2550826 |doi=10.1038/341233a0 |bibcode=1989Natur.341..233R |s2cid=699135 }}</ref> GABA can promote the replication and survival of β-cells<ref name="pmid21709230">{{cite journal |vauthors=Soltani N, Qiu H, Aleksic M, Glinka Y, Zhao F, Liu R, Li Y, Zhang N, Chakrabarti R, Ng T, Jin T, Zhang H, Lu WY, Feng ZP, Prud'homme GJ, Wang Q |title=GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=108 |issue=28 |pages=11692–7 |year=2011 |pmid=21709230 |pmc=3136292 |doi=10.1073/pnas.1102715108 |bibcode=2011PNAS..10811692S |doi-access=free }}</ref><ref name="pmid23995958">{{cite journal |vauthors=Tian J, Dang H, Chen Z, Guan A, Jin Y, Atkinson MA, Kaufman DL |title=γ-Aminobutyric acid regulates both the survival and replication of human β-cells |journal=Diabetes |volume=62 |issue=11 |pages=3760–5 |year=2013 |pmid=23995958 |pmc=3806626 |doi=10.2337/db13-0931 }}</ref><ref name="pmid25008178">{{cite journal |vauthors=Purwana I, Zheng J, Li X, Deurloo M, Son DO, Zhang Z, Liang C, Shen E, Tadkase A, Feng ZP, Li Y, Hasilo C, Paraskevas S, Bortell R, Greiner DL, Atkinson M, Prud'homme GJ, Wang Q |title=GABA promotes human β-cell proliferation and modulates glucose homeostasis |journal=Diabetes |volume=63 |issue=12 |pages=4197–205 |year=2014 |pmid=25008178 |doi=10.2337/db14-0153 |doi-access=free }}</ref> and also promote the conversion of α-cells to β-cells, which may lead to new treatments for [[diabetes]].<ref name="pmid27916274">{{cite journal |vauthors=Ben-Othman N, Vieira A, Courtney M, Record F, Gjernes E, Avolio F, Hadzic B, Druelle N, Napolitano T, Navarro-Sanz S, Silvano S, Al-Hasani K, Pfeifer A, Lacas-Gervais S, Leuckx G, Marroquí L, Thévenet J, Madsen OD, Eizirik DL, Heimberg H, Kerr-Conte J, Pattou F, Mansouri A, Collombat P |title=Long-Term GABA Administration Induces Alpha Cell-Mediated Beta-like Cell Neogenesis |journal=Cell |volume=168 |issue=1–2 |pages=73–85.e11 |year=2017 |pmid=27916274 |doi=10.1016/j.cell.2016.11.002 |doi-access=free }}</ref> Alongside GABAergic mechanisms, GABA has also been detected in other peripheral tissues including intestines, stomach, [[fallopian tubes]], [[uterus]], [[ovaries]], [[testicles]], [[kidneys]], [[urinary bladder]], the [[lungs]] and [[liver]], albeit at much lower levels than in neurons or β-cells.<ref name="pmid2405103">{{cite journal |vauthors= Erdö SL, Wolff JR |title= γ-Aminobutyric acid outside the mammalian brain |journal= J. Neurochem. |volume= 54 |issue= 2 |pages= 363–72 |date= February 1990 |pmid= 2405103 |doi= 10.1111/j.1471-4159.1990.tb01882.x|s2cid= 86144218 }}</ref> Experiments on mice have shown that hypothyroidism induced by fluoride poisoning can be halted by administering GABA. The test also found that the thyroid recovered naturally without further assistance after the fluoride had been expelled by the GABA.<ref>{{cite journal | doi = 10.1016/j.lfs.2015.12.041 | volume=146 | title=γ-Aminobutyric acid ameliorates fluoride-induced hypothyroidism in male Kunming mice | year=2016 | journal=Life Sciences | pages=1–7 | vauthors=Yang H, Xing R, Liu S, Yu H, Li P | pmid=26724496 }}</ref> [[Immune cell]]s express receptors for GABA<ref name="pmid10227421">{{cite journal |vauthors=Tian J, Chau C, Hales TG, Kaufman DL |title=GABA<sub>A</sub> receptors mediate inhibition of T cell responses |journal=J. Neuroimmunol. |volume=96 |issue=1 |pages=21–8 |year=1999 |pmid=10227421 |doi= 10.1016/s0165-5728(98)00264-1|s2cid=3006821 }}</ref><ref name="pmid22927941">{{cite journal |vauthors=Mendu SK, Bhandage A, Jin Z, Birnir B |title=Different subtypes of GABA-A receptors are expressed in human, mouse and rat T lymphocytes |journal=PLOS ONE |volume=7 |issue=8 |pages=e42959 |year=2012 |pmid=22927941 |pmc=3424250 |doi=10.1371/journal.pone.0042959 |bibcode=2012PLoSO...742959M |doi-access=free }}</ref> and administration of GABA can suppress [[inflammation|inflammatory]] immune responses and promote "regulatory" immune responses, such that GABA administration has been shown to inhibit [[autoimmune disease]]s in several animal models.<ref name="pmid21709230"/><ref name="pmid10227421"/><ref name="pmid15470076">{{cite journal |vauthors=Tian J, Lu Y, Zhang H, Chau CH, Dang HN, Kaufman DL |title=Gamma-aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model |journal=J. Immunol. |volume=173 |issue=8 |pages=5298–304 |year=2004 |pmid=15470076 |doi= 10.4049/jimmunol.173.8.5298|doi-access=free }}</ref><ref name="pmid21604972">{{cite journal |vauthors=Tian J, Yong J, Dang H, Kaufman DL |title=Oral GABA treatment downregulates inflammatory responses in a mouse model of rheumatoid arthritis |journal=Autoimmunity |volume=44 |issue=6 |pages=465–70 |year=2011 |pmid=21604972 |pmc=5787624 |doi=10.3109/08916934.2011.571223 }}</ref> In 2018, GABA was shown to regulate secretion of a greater number of cytokines. In plasma of [[T1D]] patients, levels of 26 [[cytokine]]s are increased and of those, 16 are inhibited by GABA in the cell assays.<ref>{{cite journal | vauthors = Bhandage AK, Jin Z, Korol SV, Shen Q, Pei Y, Deng Q, Espes D, Carlsson PO, Kamali-Moghaddam M, Birnir B | title = + T Cells and Is Immunosuppressive in Type 1 Diabetes | journal = eBioMedicine | volume = 30 | pages = 283–294 | date = April 2018 | pmid = 29627388 | pmc = 5952354 | doi = 10.1016/j.ebiom.2018.03.019 }}</ref> In 2007, an excitatory GABAergic system was described in the airway [[epithelium]]. The system is activated by exposure to allergens and may participate in the mechanisms of [[asthma]].<ref name="GABA_lungs">{{cite journal |vauthors= Xiang YY, Wang S, Liu M, Hirota JA, Li J, Ju W, Fan Y, Kelly MM, Ye B, Orser B, O'Byrne PM, Inman MD, Yang X, Lu WY |title= A GABAergic system in airway epithelium is essential for mucus overproduction in asthma |journal= Nat. Med. |volume= 13 |issue= 7 |pages= 862–7 |date= July 2007 |pmid= 17589520 |doi= 10.1038/nm1604|s2cid= 2461757 }}</ref> GABAergic systems have also been found in the [[testis]]<ref name="Inyerballs">{{cite book |vauthors= Payne AH, Hardy MH |title=The Leydig cell in health and disease |publisher= Humana Press|year=2007 |isbn= 978-1-58829-754-9}}</ref> and in the eye lens.<ref name="GABA_lens">{{cite journal |vauthors= Kwakowsky A, Schwirtlich M, Zhang Q, Eisenstat DD, Erdélyi F, Baranyi M, Katarova ZD, Szabó G |title= GAD isoforms exhibit distinct spatiotemporal expression patterns in the developing mouse lens: correlation with Dlx2 and Dlx5 |journal= Dev. Dyn. |volume= 236 |issue= 12 |pages= 3532–44 |date= December 2007 |pmid= 17969168 |doi= 10.1002/dvdy.21361|s2cid= 24188696 |doi-access= free }}</ref>
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