View source for Gamma-Aminobutyric acid

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{{More medical citations needed|date=June 2015}}
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{{DISPLAYTITLE:''gamma''-Aminobutyric acid}}
{{chembox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 476992474
| Name=''gamma''-Aminobutyric acid
| ImageFile = Gamma-Aminobuttersäure - gamma-aminobutyric acid.svg
| ImageSize = 230
| ImageName = Simplified structural formula
| ImageFile1 = GABA 3D ball.png
| ImageSize1 = 230
| ImageName1 = C=black, H=white, O=red, N=blue
| ImageAlt1 = GABA molecule
| PIN = 4-Aminobutanoic acid
| OtherNames=
|Section1={{Chembox Identifiers
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 2ACZ6IPC6I
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 96
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00058
| InChI = 1/C4H9NO2/c5-3-1-2-4(6)7/h1-3,5H2,(H,6,7)
| InChIKey = BTCSSZJGUNDROE-UHFFFAOYAC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C4H9NO2/c5-3-1-2-4(6)7/h1-3,5H2,(H,6,7)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = BTCSSZJGUNDROE-UHFFFAOYSA-N
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo=56-12-2
| PubChem=119
| EINECS = 200-258-6
| RTECS = ES6300000
| IUPHAR_ligand = 1067
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 116
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB02530
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 16865 
| SMILES=C(CC(=O)O)CN
| MeSHName=gamma-Aminobutyric+Acid
}}
|Section2={{Chembox Properties
| Formula=C<sub>4</sub>H<sub>9</sub>NO<sub>2</sub>
| MolarMass=103.120 g/mol
| Appearance=white microcrystalline powder
| Density=1.11&nbsp;g/mL
| MeltingPtC=203.7
| BoilingPtC=247.9
| pKa = {{ubl
 | 4.031 (carboxyl; H<sub>2</sub>O)
 | 10.556 (amino; H<sub>2</sub>O)<ref name="CRC97">{{cite book | editor= Haynes, William M. | year = 2016 | title = CRC Handbook of Chemistry and Physics | edition = 97th | publisher = [[CRC Press]] | isbn = 978-1498754286 | pages=5–88 | title-link = CRC Handbook of Chemistry and Physics }}</ref>
}}
| Solubility= 130 g/100 mL
| LogP = −3.17
}}
|Section3={{Chembox Hazards
| MainHazards= Irritant, Harmful
| FlashPt=
| AutoignitionPt =
| LD50 = 12,680&nbsp;mg/kg (mouse, oral)
}}
}}

'''''gamma-''Aminobutyric acid''', or '''γ-aminobutyric acid''' {{IPAc-en|ˈ|ɡ|æ|m|ə|_|ə|ˈ|m|iː|n|oʊ|b|juː|ˈ|t|ɪr|ᵻ|k|_|ˈ|æ|s|ᵻ|d}}, or '''GABA''' {{IPAc-en|ˈ|ɡ|æ|b|ə}}, is the chief [[inhibitory]] [[neurotransmitter]] in the developmentally mature [[mammal]]ian [[central nervous system]]. Its principal role is reducing [[neuron]]al excitability throughout the [[nervous system]]. In humans, GABA is also directly responsible for the regulation of [[muscle tone]].<ref name="pmid11837891">{{cite book |vauthors= Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H |chapter= GABA and GABA receptors in the central nervous system and other organs |title= Int. Rev. Cytol. |volume= 213 |issue= |pages= 1–47 |year= 2002 |pmid= 11837891 |doi= 10.1016/S0074-7696(02)13011-7 |chapterurl= https://books.google.com/books?id=kOV9bEuhHNEC&pg=PA1 |series= International Review of Cytology |isbn= 978-0-12-364617-0 |editor= Jeon KW}}</ref>

GABA is sold as a [[dietary supplement]].

==Function==

===Neurotransmitter===
[[File:Synapse GABA.png|thumb|GABA metabolism, involvement of glial cells]]
In [[vertebrates]], GABA acts at inhibitory [[chemical synapse|synapses]] in the [[brain]] by binding to specific transmembrane [[receptor (biochemistry)|receptor]]s in the [[plasma membrane]] of both pre- and postsynaptic neuronal processes. This binding causes the opening of [[ion channel]]s to allow the flow of either negatively charged [[chloride]] ions into the [[cell (biology)|cell]] or positively charged [[potassium]] ions out of the cell. This action results in a negative change in the [[transmembrane potential]], usually causing [[hyperpolarization (biology)|hyperpolarization]]. Two general classes of [[GABA receptor]] are known:<ref>[https://books.google.com/books?id=YggrBgAAQBAJ&pg=PT80 Generalized Non-Convulsive Epilepsy: Focus on GABA-B Receptors], C. Marescaux, M. Vergnes, R. Bernasconi</ref>
*[[GABAA receptor|GABA<sub>A</sub>]] in which the receptor is part of a [[ligand-gated ion channel]] complex
*[[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:GABAergic-synapse.gif|thumb|500px|The production, release, action, and degradation of GABA at a stereotyped GABAergic synapse]]
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}}</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}}</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. 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===
While 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 signalling 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>[https://books.google.com/books?id=rrKVDQAAQBAJ&pg=PA311 The Glutamate/GABA-Glutamine Cycle: Amino Acid Neurotransmitter Homeostasis], Arne Schousboe, Ursula Sonnewald</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= 135, box 6D |isbn= 978-0-87893-697-7 |oclc= |doi= |url= |accessdate=}}</ref><ref name="pmid16512345">{{cite book |vauthors= Jelitai M, Madarasz E |title= The role of GABA in the early neuronal development |journal= Int. Rev. Neurobiol. |volume= 71 |issue= |pages= 27–62 |year= 2005 |pmid= 16512345 |doi= 10.1016/S0074-7742(05)71002-3 |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}}</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}}</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 |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}}</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}}</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 |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|url= http://www.hal.inserm.fr/inserm-00484852 }}</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}}</ref>]]
Besides the nervous system, GABA is also produced at relatively high levels in the [[insulin]]-producing [[beta cell|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|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 |url=|bibcode=1989Natur.341..233R }}</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 |url=|bibcode=2011PNAS..10811692S }}</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 |url=}}</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 |url=}}</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 |url=}}</ref>

GABA has also been detected in other peripheral tissues including intestines, stomach, Fallopian tubes, uterus, ovaries, testes, kidneys, urinary bladder, the lungs and liver, albeit at much lower levels than in neurons or β-cells. GABAergic mechanisms have been demonstrated in various peripheral tissues and organs, which include the intestines, the stomach, the pancreas, the Fallopian tubes, the uterus, the ovaries, the testes, the kidneys, the urinary bladder, the lungs, and the liver.<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}}</ref>

[[Immune system|Immune cells]] 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|url=}}</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 |url=|bibcode=2012PLoSO...742959M }}</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|url=}}</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 |url=}}</ref>

In 2018, GABA has 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}}</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}}</ref>

GABA occurs in plants.<ref name="pmid26219411">{{cite journal |vauthors=Ramesh SA, Tyerman SD, Xu B, Bose J, Kaur S, Conn V, Domingos P, Ullah S, Wege S, Shabala S, Feijó JA, Ryan PR, Gilliham M, Gillham M |title=GABA signalling modulates plant growth by directly regulating the activity of plant-specific anion transporters |journal=Nat Commun |volume=6 |issue= |pages=7879 |year=2015 |pmid=26219411 |pmc=4532832 |doi=10.1038/ncomms8879 |url=|bibcode=2015NatCo...6.7879R}}</ref><ref name="pmid27838745">{{cite journal |vauthors=Ramesh SA, Tyerman SD, Gilliham M, Xu B |title=γ-Aminobutyric acid (GABA) signalling in plants |journal=Cell. Mol. Life Sci. |volume= 74|issue= 9|pages= 1577–1603|year=2016 |pmid=27838745 |doi=10.1007/s00018-016-2415-7 |url=}}</ref>

==Structure and conformation==
GABA is found mostly as a [[zwitterion]] (i.e. with the [[carboxyl]] group deprotonated and the amino group protonated). Its [[conformational isomerism|conformation]] depends on its environment. In the gas phase, a highly folded conformation is strongly favored due to the electrostatic attraction between the two functional groups. The stabilization is about 50 kcal/mol, according to [[quantum chemistry]] calculations. In the solid state, an extended conformation is found, with a trans conformation at the amino end and a gauche conformation at the carboxyl end. This is due to the packing interactions with the neighboring molecules. In solution, five different conformations, some folded and some extended, are found as a result of [[solvation]] effects. The conformational flexibility of GABA is important for its biological function, as it has been found to bind to different receptors with different conformations. Many GABA analogues with pharmaceutical applications have more rigid structures in order to control the binding better.<ref name="Majumdar Guha 1988">{{cite journal |vauthors= Majumdar D, Guha S |year= 1988 |title= Conformation, electrostatic potential and pharmacophoric pattern of GABA (γ-aminobutyric acid) and several GABA inhibitors |journal= Journal of Molecular Structure: THEOCHEM |volume= 180 |issue= |pages= 125–140 |doi= 10.1016/0166-1280(88)80084-8}}</ref><ref>{{cite book |vauthors= Sapse AM |title=Molecular Orbital Calculations for Amino Acids and Peptides |publisher= Birkhäuser |year= 2000 |isbn= 978-0-8176-3893-1}}{{page needed|date=May 2013}}</ref>

==History==
In 1883, GABA was first synthesized, and it was first known only as a plant and microbe metabolic product.<ref name="isbn0-19-514008-7"/>

In 1950, GABA was discovered as an integral part of the mammalian [[central nervous system]].<ref name="isbn0-19-514008-7">{{cite book |vauthors= Roth RJ, Cooper JR, Bloom FE |title= The Biochemical Basis of Neuropharmacology |publisher= Oxford University Press |location= Oxford [Oxfordshire] |year= 2003 |pages= 106 |isbn= 978-0-19-514008-8 |url= https://books.google.com/books?id=vNaM55VDoF8C&pg=PA106}}</ref>

In 1959, it was shown that at an inhibitory synapse on crayfish muscle fibers GABA acts like stimulation of the inhibitory nerve.  Both inhibition by nerve stimulation and by applied GABA are blocked by [[picrotoxin]].<ref>{{cite journal |author1=W. G. Van der Kloot |author2=J. Robbins |title=The effects of GABA and picrotoxin on the junctional potential and the contraction of crayfish muscle |journal=Experientia |date=1959 |volume=15 |page=36}}</ref>

==Biosynthesis==
[[File:Gabaergic Neurons.png|thumb|350px|GABAergic neurons which produce GABA]]

GABA is primarily synthesized from [[glutamate]] via the [[enzyme]] [[glutamate decarboxylase]] (GAD) with [[pyridoxal phosphate]] (the active form of [[vitamin B6]]) as a [[cofactor (biochemistry)|cofactor]]. This process converts glutamate (the principal [[neurotransmitter#Excitatory and inhibitory|excitatory]] neurotransmitter) into GABA (the principal inhibitory neurotransmitter).<ref name="pmid12467378">{{cite journal |vauthors= Petroff OA |title= GABA and glutamate in the human brain |journal= Neuroscientist |volume= 8 |issue= 6 |pages= 562–573 |date= December 2002 |pmid= 12467378 |doi= 10.1177/1073858402238515 |url= http://nro.sagepub.com/cgi/pmidlookup?view=long&pmid=12467378}}</ref><ref name="pmid17499106">{{cite book |vauthors= Schousboe A, Waagepetersen HS |title= GABA: homeostatic and pharmacological aspects |journal= Prog. Brain Res. |volume= 160 |issue= |pages= 9–19 |year= 2007 |pmid= 17499106 |doi= 10.1016/S0079-6123(06)60002-2 |isbn= 978-0-444-52184-2 |series= Progress in Brain Research}}</ref>

GABA can also be synthesized from putrescine<ref name=":0">{{Cite journal|last=Krantis|first=Anthony|date=2000-12-01|title=GABA in the Mammalian Enteric Nervous System|journal=Physiology|volume=15|issue=6|pages=284–290|doi=10.1152/physiologyonline.2000.15.6.284|issn=1548-9213}}</ref><ref>{{Cite journal|last=Sequerra|first=E. B.|last2=Gardino|first2=P.|last3=Hedin-Pereira|first3=C.|last4=de Mello|first4=F. G.|date=2007-05-11|title=Putrescine as an important source of GABA in the postnatal rat subventricular zone|journal=Neuroscience|volume=146|issue=2|pages=489–493|doi=10.1016/j.neuroscience.2007.01.062|pmid=17395389|issn=0306-4522}}</ref> by diamine oxidase and aldehyde dehydrogenase.<ref name=":0" />

Traditionally it was thought that exogenous GABA did not penetrate the blood–brain barrier,<ref name=Kuriyama>{{cite journal |vauthors= Kuriyama K, Sze PY |title= Blood–brain barrier to H3-γ-aminobutyric acid in normal and amino oxyacetic acid-treated animals |journal= Neuropharmacology |volume= 10 |issue= 1 |pages= 103–108 |date= January 1971 |pmid= 5569303 |doi= 10.1016/0028-3908(71)90013-X}}</ref> however more current research<ref>{{cite journal |pmc=4594160 |pmid=26500584 |doi=10.3389/fpsyg.2015.01520 |volume=6 |title=Neurotransmitters as food supplements: the effects of GABA on brain and behavior |year=2015 |journal=Front Psychol |page=1520 |vauthors=Boonstra E, de Kleijn R, Colzato LS, Alkemade A, Forstmann BU, Nieuwenhuis S}}</ref> indicates that it may be possible, or that exogenous GABA (i.e. in the form of nutritional supplements) could exert GABAergic effects on the [[enteric nervous system]] which in turn stimulate endogenous GABA production. The direct involvement of GABA in the [[glutamate–glutamine cycle]] makes the question of whether GABA can penetrate the blood-brain barrier somewhat misleading, because both glutamate and glutamine can freely cross the barrier and convert to GABA within the brain.

==Catabolism==
[[GABA transaminase]] enzyme catalyzes the conversion of 4-aminobutanoic acid (GABA) and 2-oxoglutarate (α-ketoglutarate) into [[succinic semialdehyde]] and glutamate. Succinic semialdehyde is then [[oxidation|oxidized]] into [[succinic acid]] by [[succinic semialdehyde dehydrogenase]] and as such enters the [[citric acid cycle]] as a usable source of energy.<ref name=catabolism>{{cite journal |vauthors= Bown AW, Shelp BJ |title= The Metabolism and Functions of γ-Aminobutyric Acid |journal= Plant Physiol. |volume= 115 |issue= 1 |pages= 1–5 |date= September 1997 |pmid= 12223787 |pmc= 158453 |doi= 10.1104/pp.115.1.1}}</ref>

==Pharmacology==
Drugs that act as [[allosteric modulator]]s of [[GABA receptor]]s (known as GABA analogues or ''GABAergic'' drugs), or increase the available amount of GABA, typically have relaxing, anti-anxiety, and anti-convulsive effects.<ref name="pmid16377242">{{cite journal |vauthors= Foster AC, Kemp JA |title= Glutamate- and GABA-based CNS therapeutics |journal= Curr Opin Pharmacol |volume= 6 |issue= 1 |pages= 7–17 |date= February 2006 |pmid= 16377242 |doi= 10.1016/j.coph.2005.11.005}}</ref><ref name="pmid11583788">{{cite journal |vauthors= Chapouthier G, Venault P |title= A pharmacological link between epilepsy and anxiety? |journal= Trends Pharmacol. Sci. |volume= 22 |issue= 10 |pages= 491–3 |date= October 2001 |pmid= 11583788 |doi= 10.1016/S0165-6147(00)01807-1}}</ref> Many of the substances below are known to cause [[anterograde amnesia]] and [[retrograde amnesia]].<ref name="pmid12761368">{{cite journal |vauthors= Campagna JA, Miller KW, Forman SA |title= Mechanisms of actions of inhaled anesthetics |journal= N. Engl. J. Med. |volume= 348 |issue= 21 |pages= 2110–24 |date= May 2003 |pmid= 12761368 |doi= 10.1056/NEJMra021261}}</ref>

In general, GABA does not cross the [[blood–brain barrier]],<ref name="Kuriyama"/> although certain areas of the brain that have no effective blood–brain barrier, such as the [[periventricular nucleus]], can be reached by drugs such as systemically injected GABA.<ref name=Muller1999/> At least one study suggests that orally administered GABA increases the amount of [[human growth hormone]] (HGH).<ref name=Powers2008>{{cite journal |vauthors= Powers ME, Yarrow JF, McCoy SC, Borst SE |title= Growth hormone isoform responses to GABA ingestion at rest and after exercise |journal= Medicine and Science in Sports and Exercise |volume= 40 |issue= 1 |pages= 104–10 |date= January 2008 |pmid= 18091016 |doi= 10.1249/mss.0b013e318158b518}}</ref> GABA directly injected to the brain has been reported to have both stimulatory and inhibitory effects on the production of growth hormone, depending on the physiology of the individual.<ref name="Muller1999">{{cite journal |vauthors= Müller EE, Locatelli V, Cocchi D |title= Neuroendocrine control of growth hormone secretion |journal= Physiol. Rev. |volume= 79 |issue= 2 |pages= 511–607 |date= April 1999 |pmid= 10221989 |doi= 10.1152/physrev.1999.79.2.511}}</ref> Certain pro-drugs of GABA (ex. [[picamilon]]) have been developed to permeate the blood–brain barrier, then separate into GABA and the carrier molecule once inside the brain. Prodrugs allow for a direct increase of GABA levels throughout all areas of the brain, in a manner following the distribution pattern of the pro-drug prior to metabolism.{{citation needed|date=September 2016}}

GABA enhanced the catabolism of serotonin into [[N-acetylserotonin|''N''-acetylserotonin]] (the precursor of [[melatonin]]) in rats.<ref name="pmid6844712">{{cite journal |vauthors= Balemans MG, Mans D, Smith I, Van Benthem J |title= The influence of GABA on the synthesis of N-acetylserotonin, melatonin, O-acetyl-5-hydroxytryptophol and O-acetyl-5-methoxytryptophol in the pineal gland of the male Wistar rat |journal= Reproduction, Nutrition, Development |volume= 23 |issue= 1 |pages= 151–60 |year= 1983 |pmid= 6844712 |doi= 10.1051/rnd:19830114}}</ref> It is thus suspected that GABA is involved in the synthesis of melatonin and thus might exert regulatory effects on sleep and reproductive functions.<ref>{{cite journal |vauthors= Sato S, Yinc C, Teramoto A, Sakuma Y, Kato M |title= Sexually dimorphic modulation of GABA(A) receptor currents by melatonin in rats gonadotropin–releasing hormone neurons |journal= J Physiol Sci |volume= 58 |issue= 5 |pages= 317–322 |date= 2008 |doi=10.2170/physiolsci.rp006208|pmid= 18834560 }}</ref>

==Chemistry==
Although in chemical terms, GABA is an [[amino acid]] (as it has both a primary amine and a carboxylic acid functional group), it is rarely referred to as such in the professional, scientific, or medical community. By convention the term "amino acid", when used without a [[qualifier]], refers specifically to an [[alpha amino acid]]. GABA is not an alpha amino acid, meaning the amino group is not attached to the alpha carbon so it is not incorporated into [[proteins]].<ref>[https://books.google.com/books?id=SDi2BQAAQBAJ&pg=RA1-PA435 The Brain, the Nervous System, and Their Diseases &#91;3 volumes&#93;], Jennifer L. Hellier</ref>

==[[GABAergic]] drugs==

GABA<sub>A</sub> receptor ligands are shown in the following table{{refn|group=nb|Many more GABA<sub>A</sub> ligands are listed at [[Template:GABA receptor modulators]] and at [[GABAA receptor#Ligands]]}}
:

{| class="wikitable"
|-
!'''Activity at GABA<sub>A</sub>''' !! '''Ligand'''
|-
|Orthosteric Agonist
|[[Muscimol]],<ref name="pmid28528665">{{cite book | vauthors = Chua HC, Chebib M | title = GABAA Receptors and the Diversity in their Structure and Pharmacology | journal = Advances in Pharmacology (San Diego, Calif.) | volume = 79 | issue = | pages = 1–34 | date = 2017 | pmid = 28528665 | doi = 10.1016/bs.apha.2017.03.003 | series = Advances in Pharmacology | isbn = 9780128104132 }}</ref> GABA,<ref name="pmid28528665"/> gaboxadol ([[THIP]]),<ref name="pmid28528665"/> [[isoguvacine]], [[progabide]], piperidine-4-sulfonic acid (partial agonist)
|-
|[[GABAA receptor positive allosteric modulator|Positive allosteric modulators]]
|[[Barbiturate]]s,<ref name="Loescher&Rogawski">{{Cite journal | last1 = Löscher | first1 = W. | last2 = Rogawski | first2 = M. A. | doi = 10.1111/epi.12025 | title = How theories evolved concerning the mechanism of action of barbiturates | journal = Epilepsia | volume = 53 | pages = 12–25 | year = 2012 | pmid = 23205959 }}</ref> [[benzodiazepine]]s,<ref name="isbn0-12-088397-X">{{cite book |vauthors=Olsen RW, Betz H |veditors=Siegel GJ, Albers RW, Brady S, Price DD |title=Basic Neurochemistry: Molecular, Cellular and Medical Aspects |edition=7th |publisher=Elsevier |year=2006 |pages=291–302 |chapter=GABA and glycine |isbn=978-0-12-088397-4 }}</ref> [[neuroactive steroid]]s<ref name="neuroactive_steroid">(a) {{cite journal | vauthors = Herd MB, Belelli D, Lambert JJ | title = Neurosteroid modulation of synaptic and extrasynaptic GABA(A) receptors | journal = Pharmacology & Therapeutics | volume = 116 | issue = 1 | pages = 20–34 | date = October 2007 | pmid = 17531325 | doi = 10.1016/j.pharmthera.2007.03.007 | url = http://www.journals.elsevier.com/pharmacology-and-therapeutics }}; (b) {{cite journal | vauthors = Hosie AM, Wilkins ME, da Silva HM, Smart TG | title = Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites | journal = Nature | volume = 444 | issue = 7118 | pages = 486–9 | date = November 2006 | pmid = 17108970 | doi = 10.1038/nature05324 }}; (c){{cite journal | vauthors = Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A | title = Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 39 | pages = 14602–7 | date = September 2006 | pmid = 16984997 | pmc = 1600006 | doi = 10.1073/pnas.0606544103 }}; (d) {{cite journal | vauthors = Akk G, Shu HJ, Wang C, Steinbach JH, Zorumski CF, Covey DF, Mennerick S | title = Neurosteroid access to the GABAA receptor | journal = The Journal of Neuroscience | volume = 25 | issue = 50 | pages = 11605–13 | date = December 2005 | pmid = 16354918 | doi = 10.1523/JNEUROSCI.4173-05.2005 }}; (e) {{cite journal | vauthors = Belelli D, Lambert JJ | title = Neurosteroids: endogenous regulators of the GABA(A) receptor | journal = Nature Reviews. Neuroscience | volume = 6 | issue = 7 | pages = 565–75 | date = July 2005 | pmid = 15959466 | doi = 10.1038/nrn1703 }}; (f) {{cite journal | vauthors = Pinna G, Costa E, Guidotti A | title = Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake | journal = Psychopharmacology | volume = 186 | issue = 3 | pages = 362–72 | date = June 2006 | pmid = 16432684 | doi = 10.1007/s00213-005-0213-2 }}; (g) {{cite journal | vauthors = Dubrovsky BO | title = Steroids, neuroactive steroids and neurosteroids in psychopathology | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 29 | issue = 2 | pages = 169–92 | date = February 2005 | pmid = 15694225 | doi = 10.1016/j.pnpbp.2004.11.001 }}; (h) {{cite journal | vauthors = Mellon SH, Griffin LD | title = Neurosteroids: biochemistry and clinical significance | journal = Trends in Endocrinology and Metabolism | volume = 13 | issue = 1 | pages = 35–43 | year = 2002 | pmid = 11750861 | doi = 10.1016/S1043-2760(01)00503-3 }}; (i) {{cite journal | vauthors = Puia G, Santi MR, Vicini S, Pritchett DB, Purdy RH, Paul SM, Seeburg PH, Costa E | title = Neurosteroids act on recombinant human GABAA receptors | journal = Neuron | volume = 4 | issue = 5 | pages = 759–65 | date = May 1990 | pmid = 2160838 | doi = 10.1016/0896-6273(90)90202-Q }}; (j) {{cite journal | vauthors = Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM | title = Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor | journal = Science | volume = 232 | issue = 4753 | pages = 1004–7 | date = May 1986 | pmid = 2422758 | doi = 10.1126/science.2422758 | url = https://zenodo.org/record/1230988 }}; (k) {{cite book |vauthors=Reddy DS, Rogawski MA | chapter = Neurosteroids — Endogenous Regulators of Seizure Susceptibility and Role in the Treatment of Epilepsy |veditors=Noebels JL, Avoli M, Rogawski MA |title = Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US) | date = 2012 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK98218/|display-editors=etal| publisher = National Center for Biotechnology Information (US) }}</ref> [[niacin]]/[[niacinamide]],<ref>{{cite journal|last=Toraskar|first=Mrunmayee|author2=Pratima R.P. Singh |author3=Shashank Neve |title=STUDY OF GABAERGIC AGONISTS|journal=Deccan Journal of Pharmacology|year=2010|volume=1|issue=2|pages=56–69|url=http://www.ijdpls.com/uploaded/journal_files/120402040442.pdf}}</ref> [[nonbenzodiazepines]] (i.e. z-drugs, e.g. [[zolpidem]], [[eszopiclone]]){{citation needed|date=April 2019}}, [[etomidate]],<ref>{{cite book | last1 = Vanlersberghe | first1 = C | last2 = Camu | first2 = F | title = Etomidate and other non-barbiturates | volume = 182 | issue = 182 | pages = 267–82 | year = 2008 | pmid = 18175096 | doi = 10.1007/978-3-540-74806-9_13 | series = Handbook of Experimental Pharmacology | isbn = 978-3-540-72813-9 }}</ref> [[etaqualone]]{{citation needed|date=April 2019}}, [[alcohol (drug)|alcohol]] ([[ethanol]]),<ref name="pmid12692303">{{cite journal |vauthors= Dzitoyeva S, Dimitrijevic N, Manev H |title= γ-aminobutyric acid B receptor 1 mediates behavior-impairing actions of alcohol in ''Drosophila'': adult RNA interference and pharmacological evidence |journal= Proc. Natl. Acad. Sci. U.S.A. |volume= 100 |issue= 9 |pages= 5485–5490 |year= 2003 |pmid= 12692303 |pmc= 154371 |doi= 10.1073/pnas.0830111100 |bibcode= 2003PNAS..100.5485D}}</ref><ref name="pmid9311780">{{cite journal |vauthors= Mihic SJ, Ye Q, Wick MJ, Koltchine VV, Krasowski MD, Finn SE, Mascia MP, Valenzuela CF, Hanson KK, Greenblatt EP, Harris RA, Harrison NL |title= Sites of alcohol and volatile anaesthetic action on GABA<sub>A</sub> and glycine receptors |journal= Nature |volume= 389 |issue= 6649 |pages= 385–389 |year= 1997 |pmid= 9311780 |doi= 10.1038/38738 |bibcode= 1997Natur.389..385M}}</ref><ref name="pmid17175815">{{cite journal |vauthors= Boehm SL, Ponomarev I, Blednov YA, Harris RA |title= From gene to behavior and back again: new perspectives on GABA<sub>A</sub>receptor subunit selectivity of alcohol actions |journal= Adv. Pharmacol. |volume= 54 |issue= 8 |pages= 1581–1602 |year= 2006 |pmid= 17175815 |doi= 10.1016/j.bcp.2004.07.023}}</ref> [[theanine]] {{citation needed|date=April 2019}}, [[methaqualone]], [[propofol]], [[stiripentol]],<ref>{{cite journal | vauthors = Fisher JL | title = The anti-convulsant stiripentol acts directly on the GABA(A) receptor as a positive allosteric modulator | journal = Neuropharmacology | volume = 56 | issue = 1 | pages = 190–7 | date = January 2009 | pmid = 18585399 | pmc = 2665930 | doi = 10.1016/j.neuropharm.2008.06.004 }}</ref> and anaesthetics<ref name="pmid28528665"/> (including [[volatile anaesthetics]]), [[glutethimide]]{{citation needed|date=April 2019}}
|-
|[[Receptor antagonist#Competitive|Orthosteric (competitive) Antagonist]]
| [[bicuculline]],<ref name="pmid28528665"/> [[gabazine]],<ref>{{cite journal|pmid=8987785|year=1997|last1=Ueno|first1=S|last2=Bracamontes|first2=J|last3=Zorumski|first3=C|last4=Weiss|first4=DS|last5=Steinbach|first5=JH|title=Bicuculline and gabazine are allosteric inhibitors of channel opening of the GABAA receptor|volume=17|issue=2|pages=625–34|journal=The Journal of Neuroscience|doi=10.1523/jneurosci.17-02-00625.1997}}</ref> [[thujone]],<ref>{{cite journal | author = Olsen RW | title = Absinthe and gamma-aminobutyric acid receptors | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 9 | pages = 4417–8 | date = April 2000 | pmid = 10781032 | pmc = 34311 | doi = 10.1073/pnas.97.9.4417 }}</ref> [[flumazenil]]<ref>{{Cite journal|title = Pharmacology of flumazenil|journal = Acta Anaesthesiologica Scandinavica. Supplementum|date = 1995-01-01|issn = 0515-2720|pmid = 8693922|pages = 3–14|volume = 108|first = J. G.|last = Whitwam|first2 = R.|last2 = Amrein}}</ref>
|-
|[[Uncompetitive antagonist]] (e.g. channel blocker)
|[[picrotoxin]]{{citation needed|date=April 2019}}, [[cicutoxin]]
|-
|[[allosteric regulation#Allosteric modulation|Negative allosteric modulators]]
| [[neuroactive steroid]]s{{citation needed|date=April 2019}} ([[Pregnenolone sulfate]] {{citation needed|date=April 2019}}), [[furosemide]], [[oenanthotoxin]], [[amentoflavone]]
|-
|}

Additionally, [[carisoprodol]] is an enhancer of GABA<sub>A</sub> activity {{citation needed|date=April 2019}}. [[Ro15-4513]] is a reducer of GABA<sub>A</sub> activity {{citation needed|date=April 2019}}.

GABAergic pro-drugs include [[chloral hydrate]], which is metabolised to [[trichloroethanol]],<ref name=Ull>{{Ullmann|first1=Reinhard |last1=Jira |first2=Erwin |last2=Kopp |first3=Blaine C. |last3=McKusick |first4=Gerhard |last4=Röderer |first5=Axel |last5=Bosch |first6=Gerald |last6=Fleischmann |title=Chloroacetaldehydes |doi=10.1002/14356007.a06_527.pub2}}</ref> which then acts via the GABA<sub>A</sub> receptor.<ref>{{cite journal |pmid=17557503 |year=2006 |last1=Lu |first1=J. |last2=Greco |first2=M. A. |title=Sleep circuitry and the hypnotic mechanism of GABA<sub>A</sub> drugs |volume=2 |issue=2 |pages=S19–S26 |journal=Journal of Clinical Sleep Medicine}}</ref>

[[Scutellaria lateriflora|Skullcap]] and [[valerian (herb)|valerian]] are plants containing GABAergic substances {{citation needed|date=April 2019}}. Furthermore, the plant [[kava]] contains GABAergic compounds, including kavain, dihydrokavain, methysticin, dihydromethysticin and yangonin.<ref name="pmid12383029">{{cite journal | vauthors = Singh YN, Singh NN | title = Therapeutic potential of kava in the treatment of anxiety disorders | journal = CNS Drugs | volume = 16 | issue = 11 | pages = 731–43 | year = 2002 | pmid = 12383029 | doi = 10.2165/00023210-200216110-00002| url = }}</ref>

Other GABAergic modulators include:

*GABA<sub>B</sub> receptor ligands.{{citation needed|date=September 2016}}
**Agonists: [[baclofen]], [[gamma-Butyrolactone|GBL]], [[propofol]], [[gamma-Hydroxybutyric acid|GHB]],<ref name="pmid16129424">{{cite journal |vauthors= Dimitrijevic N, Dzitoyeva S, Satta R, Imbesi M, Yildiz S, Manev H |title= ''Drosophila'' GABA<sub>B</sub> receptors are involved in behavioral effects of gamma-hydroxybutyric acid (GHB) |journal= Eur. J. Pharmacol. |volume= 519 |issue= 3 |pages= 246–252 |year= 2005 |pmid= 16129424 |doi= 10.1016/j.ejphar.2005.07.016}}</ref> [[phenibut]].
**Antagonists: [[phaclofen]], [[saclofen]].
*[[GABA reuptake inhibitor]]s: [[deramciclane]], [[hyperforin]], [[tiagabine]].{{citation needed|date=September 2016}}
*[[GABA transaminase inhibitor]]s: [[gabaculine]], [[phenelzine]], [[valproate]], [[vigabatrin]], [[lemon balm]] (''Melissa officinalis'').<ref name="pmid19165747">{{cite journal |vauthors= Awad R, Muhammad A, Durst T, Trudeau VL, Arnason JT |title= Bioassay-guided fractionation of lemon balm (''Melissa officinalis'' L.) using an in vitro measure of GABA transaminase activity |journal= Phytother Res |volume= 23 |issue= 8 |pages= 1075–81 |date= August 2009 |pmid= 19165747 |doi= 10.1002/ptr.2712}}</ref>
*[[GABA analogue]]s: [[pregabalin]], [[gabapentin]],<ref name="pmid21296127">{{cite journal |vauthors= Celikyurt IK, Mutlu O, Ulak G, Akar FY, Erden F |title= Gabapentin, A GABA analogue, enhances cognitive performance in mice |journal= Neuroscience Letters |volume= 492 |issue= 2 |pages= 124–8 |year= 2011 |pmid= 21296127 |doi= 10.1016/j.neulet.2011.01.072|bibcode= 2006NeuL..400..197D }}</ref> [[picamilon]], [[progabide]]{{citation needed|date=September 2016}}

== In plants ==
GABA is also found in plants. It is the most abundant amino acid in the [[apoplast]] of tomatoes.<ref>{{cite journal |vauthors= Park DH, Mirabella R, Bronstein PA, Preston GM, Haring MA, Lim CK, Collmer A, Schuurink RC |title= Mutations in γ-aminobutyric acid (GABA) transaminase genes in plants or ''Pseudomonas syringae'' reduce bacterial virulence |journal= Plant J. |volume= 64 |issue= 2 |pages= 318–30 |date= October 2010 |pmid= 21070411 |doi= 10.1111/j.1365-313X.2010.04327.x}}</ref> Evidence also suggests a role in cell signalling in plants.<ref name="pmid15003233">{{cite journal |vauthors= Bouché N, Fromm H |title= GABA in plants: just a metabolite? |journal= Trends Plant Sci. |volume= 9 |issue= 3 |pages= 110–5 |date= March 2004 |pmid= 15003233 |doi= 10.1016/j.tplants.2004.01.006}}</ref><ref name="pmid19704616">{{cite journal |vauthors= Roberts MR |title= Does GABA Act as a Signal in Plants?: Hints from Molecular Studies |journal= Plant Signal Behav |volume= 2 |issue= 5 |pages= 408–9 |date= September 2007 |pmid= 19704616 |pmc= 2634229 |doi= 10.4161/psb.2.5.4335}}</ref>

==See also==
*[[GABA receptor]]
*[[Giant depolarizing potential]]
*[[Spasticity]]
*[[Spastic diplegia]], a GABA deficiency [[neuromuscular]] [[neuropathology]]
*[[GABA tea]]
*[[GABA analogue]]
*[[Succinic semialdehyde dehydrogenase deficiency]]
*[[4-aminobutyrate transaminase]] (GABA-transaminase) deficiency

==Notes==
{{reflist|group=nb}}

==References==
{{Reflist|32em}}

==External links==
{{Commons category|Gamma-Aminobutyric acid}}
*{{cite journal |vauthors= Parviz M, Vogel K, Gibson KM, Pearl PL |date= 2014-11-25 |title= Disorders of GABA metabolism: SSADH and GABA-transaminase deficiencies |journal= Journal of Pediatric Epilepsy |quote= Clinical disorders known to affect inherited GABA metabolism |pmc=4256671 |pmid= 25485164 |doi=10.3233/PEP-14097 |volume=3 |issue= 4 |pages= 217–227}}
*[http://gmd.mpimp-golm.mpg.de/Spectrums/499427bb-2409-44f0-ad19-815033a33710.aspx Gamma-aminobutyric acid MS Spectrum]
*[http://www.scholarpedia.org/article/Gamma-aminobutyric_acid Scholarpedia article on GABA]
*[http://neurolex.org/wiki/GABAergic_Neurons List of GABA neurons on NeuroLex.org]

{{Non-proteinogenic amino acids}}
{{Neurotransmitters}}
{{GABA receptor modulators}}
{{GABA metabolism and transport modulators}}
{{Authority control}}

{{DEFAULTSORT:Aminobutyric Acid, Gamma-}}
[[Category:Neurotransmitters]]
[[Category:Amino acids]]
[[Category:GABA analogues|*]]
[[Category:GABA receptor agonists]]
[[Category:Glycine receptor agonists]]<!--PMID: 18304476-->
[[Category:Biology of obsessive–compulsive disorder]]<!--http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3762604/-->
[[Category:Peripherally selective drugs]]
[[Category:GABA| ]]
[[Category:Non-proteinogenic amino acids]]