GABA

Two general classes of GABA receptor are known:{{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}}

• GABA_A in which the receptor is part of a ligand-gated ion channel complex{{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_A 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}}
• GABA_B metabotropic receptors, which are G protein-coupled receptors that open or close ion channels via intermediaries (G proteins)

File:Release, Reuptake, and Metabolism Cycle of GABA.png

Neurons that produce GABA as their output are called GABAergic neurons, and have chiefly inhibitory action at receptors in the adult vertebrate. Medium spiny cells are a typical example of inhibitory central nervous system GABAergic cells. In contrast, GABA exhibits both excitatory and inhibitory actions in insects, mediating muscle activation at synapses between nerves and muscle cells, and also the stimulation of certain glands.{{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 }} In mammals, some GABAergic neurons, such as chandelier cells, are also able to excite their glutamatergic counterparts.{{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 }} In addition to fast-acting phasic inhibition, small amounts of extracellular GABA can induce slow timescale tonic inhibition on neurons.{{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}}

GABA_A 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 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.{{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}}

GABA is an inhibitory transmitter in the mature brain; its actions were thought to be primarily excitatory in the developing brain.{{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}} 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⁻ 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 maturation of glutamatergic synapses.{{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}}

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.{{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 }}{{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}} The ganglionic eminences also contribute greatly to building up the GABAergic cortical cell population.{{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 }}

GABA regulates the proliferation of neural progenitor cells,{{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 }}{{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}} the migration{{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}} and differentiation{{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 }}{{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 }} the elongation of neurites{{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⁻ 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}} and the formation of synapses.{{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 }}

GABA also regulates the growth of embryonic and neural stem cells. GABA can influence the development of neural progenitor cells via brain-derived neurotrophic factor (BDNF) expression.{{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}} GABA activates the GABA_A receptor, causing cell cycle arrest in the S-phase, limiting growth.{{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}}

File:Autoradiography of a brain slice from an embryonal rat - PMID19190758 PLoS 0004371.png in a coronal brain section of a one-day-old Wistar rat, with the highest expression in subventricular zone (svz){{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 }}]]

Besides the nervous system, GABA is also produced at relatively high levels in the insulin-producing beta cells (β-cells) of the pancreas. The β-cells secrete GABA along with insulin and the GABA binds to GABA receptors on the neighboring islet alpha cells (α-cells) and inhibits them from secreting glucagon (which would counteract insulin's effects).{{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_A-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 }}

GABA can promote the replication and survival of β-cells{{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 }}{{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 }}{{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 }} and also promote the conversion of α-cells to β-cells, which may lead to new treatments for diabetes.{{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 }}

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.{{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 }}

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.{{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 }}

Immune cells express receptors for GABA{{cite journal |vauthors=Tian J, Chau C, Hales TG, Kaufman DL |title=GABA_A 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 }}{{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 }} and administration of GABA can suppress inflammatory immune responses and promote "regulatory" immune responses, such that GABA administration has been shown to inhibit autoimmune diseases in several animal models.{{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 }}{{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 }}

In 2018, GABA was shown to regulate secretion of a greater number of cytokines. In plasma of T1D patients, levels of 26 cytokines are increased and of those, 16 are inhibited by GABA in the cell assays.{{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 }}

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.{{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 }} GABAergic systems have also been found in the testis{{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}} and in the eye 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 }}

GABA is found mostly as a zwitterion (i.e., with the carboxyl group deprotonated and the amino group protonated). Its 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.{{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 |pages= 125–140 |doi= 10.1016/0166-1280(88)80084-8}}{{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}}

GABA was first synthesized in 1883; it was first known only as a plant and microbe metabolic product.{{cite book |url=https://books.google.com/books?id=vNaM55VDoF8C&pg=PA106 |title=The Biochemical Basis of Neuropharmacology |vauthors=Roth RJ, Cooper JR, Bloom FE |publisher=Oxford University Press |year=2003 |isbn=978-0-19-514008-8 |location=Oxford [Oxfordshire] |pages=106}}

In 1950, Washington University School of Medicine researchers Eugene Roberts and Sam Frankel used newly-developed techniques of chromatography to analyze protein-free extracts of mammalian brain. They discovered that GABA is metabolized from glutamic acid and accumulates in the mammalian central nervous system.{{Cite journal |last=Spiering |first=Martin J. |date=December 2018 |title=The discovery of GABA in the brain |url=https://www.asbmb.org/asbmb-today/science/010119/jbc-the-discovery-of-gaba-in-the-brain |journal=Journal of Biological Chemistry |volume=293 |issue=49 |pages=19159–19160 |doi=10.1074/jbc.cl118.006591 |issn=0021-9258 |pmc=6295731 |pmid=30530855 |doi-access=free}}{{Cite journal |last1=Roberts |first1=E. |last2=Frankel |first2=S. |date=November 1950 |title=gamma-Aminobutyric acid in brain: its formation from glutamic acid |journal=The Journal of Biological Chemistry |volume=187 |issue=1 |pages=55–63 |doi=10.1016/S0021-9258(19)50929-2 |doi-access=free |issn=0021-9258 |pmid=14794689}}

There was not much further research into the substance until 1957; Canadian researchers identified GABA as the mysterious component (termed Factor I by its discoverers in 1954) of brain and spinal cord extracts which inhibited crayfish neurons.{{Cite journal |last1=Bazemore |first1=A. W. |last2=Elliott |first2=K. A. C. |last3=Florey |first3=E. |date=August 1957 |title=Isolation of Factor I |url=https://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.1957.tb12090.x |journal=Journal of Neurochemistry |language=en |volume=1 |issue=4 |pages=334–339 |doi=10.1111/j.1471-4159.1957.tb12090.x |pmid=13476199 |issn=0022-3042|url-access=subscription }}

In 1959, it was shown that, at an inhibitory synapse on crayfish muscle fibers, GABA acts through stimulation of the inhibitory nerve. Both inhibition by nerve stimulation and by applied GABA are blocked by picrotoxin.{{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}}

File:Gabaergic Neurons.png

GABA is primarily synthesized from glutamate via the enzyme glutamate decarboxylase (GAD) with pyridoxal phosphate (the active form of vitamin B6) as a cofactor. This process converts glutamate (the principal excitatory neurotransmitter) into GABA (the principal inhibitory neurotransmitter).{{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 |s2cid= 84891972 }}{{cite conference |vauthors= Schousboe A, Waagepetersen HS |chapter= GABA: Homeostatic and pharmacological aspects |title= Gaba and the Basal Ganglia - from Molecules to Systems |volume= 160 |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}}

GABA can also be synthesized from putrescine{{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|pmid=11390928|issn=1548-9213}}{{Cite journal|last1=Sequerra|first1=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|s2cid=43003476|issn=0306-4522}} by diamine oxidase and aldehyde dehydrogenase.

Historically it was thought that exogenous GABA did not penetrate the blood–brain barrier,{{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}} but more current research{{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|doi-access=free }} describes the notion as being unclear pending further research.

GABA transaminase enzymes catalyze the conversion of 4-aminobutanoic acid (GABA) and 2-oxoglutarate (α-ketoglutarate) into succinic semialdehyde and glutamate. Succinic semialdehyde is then oxidized into succinic acid by succinic semialdehyde dehydrogenase and as such enters the citric acid cycle as a usable source of energy.{{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}}

Drugs that act as allosteric modulators of GABA receptors (known as GABA analogues or GABAergic drugs), or increase the available amount of GABA, typically have relaxing, anti-anxiety, and anti-convulsive effects (with equivalent efficacy to lamotrigine based on studies of mice).{{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}}{{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}} Many of the substances below are known to cause anterograde amnesia and retrograde amnesia.{{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}}

In general, GABA does not cross the blood–brain barrier, 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. At least one study suggests that orally administered GABA increases the amount of human growth hormone (HGH).{{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|s2cid= 24907247 |doi-access= free }} 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.{{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}} Consequently, considering the potential biphasic effects of GABA on growth hormone production, as well as other safety concerns, its usage is not recommended during pregnancy and lactation.{{cite journal |vauthors=Oketch-Rabah HA, Madden EF, Roe AL, Betz JM |title=United States Pharmacopeia (USP) Safety Review of Gamma-Aminobutyric Acid (GABA) |journal=Nutrients |volume=13 |issue=8 |date=August 2021 |page=2742 |pmid=34444905 |pmc=8399837 |doi=10.3390/nu13082742 |url=|doi-access=free }}

GABA enhances the catabolism of serotonin into N-acetylserotonin (the precursor of melatonin) in rats.{{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|doi-access= free }} It is thus suspected that GABA is involved in the synthesis of melatonin and thus might exert regulatory effects on sleep and reproductive functions.{{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= The Journal of Physiological Sciences |volume= 58 |issue= 5 |pages= 317–322 |date= 2008 |doi=10.2170/physiolsci.rp006208|pmid= 18834560 |doi-access= free }}

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. Nor is it incorporated into proteins as are many alpha-amino acids.{{Cite book|last=Hellier|first=Jennifer L.|url=https://books.google.com/books?id=SDi2BQAAQBAJ&pg=RA1-PA435|title=The Brain, the Nervous System, and Their Diseases [3 volumes]|date=2014-12-16|publisher=ABC-CLIO|isbn=978-1-61069-338-7|language=en}}

GABA_A receptor ligands are shown in the following table.{{refn|group=nb|Many more GABA_A ligands are listed at Template:GABA receptor modulators and at GABAA receptor#Ligands.}}

GABAergic pro-drugs include chloral hydrate, which is metabolised to trichloroethanol,{{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}} which then acts via the GABA_A receptor.{{cite journal |pmid=17557503 |year=2006 |last1=Lu |first1=J. |last2=Greco |first2=M. A. |title=Sleep circuitry and the hypnotic mechanism of GABA_A drugs |volume=2 |issue=2 |pages=S19–S26 |journal=Journal of Clinical Sleep Medicine|doi=10.5664/jcsm.26527 |doi-access=free }}

The plant kava contains GABAergic compounds, including kavain, dihydrokavain, methysticin, dihydromethysticin and yangonin.{{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| s2cid = 34322458 }}

{{More medical citations needed |section|date=June 2015}}

Other GABAergic modulators include:

• GABA_B receptor ligands.{{citation needed|date=September 2016}}
• Agonists: baclofen, propofol, GHB,{{cite journal |vauthors= Dimitrijevic N, Dzitoyeva S, Satta R, Imbesi M, Yildiz S, Manev H |title= Drosophila GABA_B 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}} phenibut.
• Antagonists: phaclofen, saclofen.
• GABA reuptake inhibitors: deramciclane, hyperforin, tiagabine.{{citation needed|date=September 2016}}
• GABA transaminase inhibitors: gabaculine, phenelzine, valproate, vigabatrin, lemon balm (Melissa officinalis).{{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|s2cid= 23127112 }}
• GABA analogues: pregabalin, gabapentin,{{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 |s2cid= 8303292 }} picamilon, progabide{{citation needed|date=September 2016}}

4-Amino-1-butanol is a biochemical precursor of GABA and can be converted into GABA by the actions of aldehyde reductase (ALR) and aldehyde dehydrogenase (ALDH) with γ-aminobutyraldehyde (GABAL) as a metabolic intermediate.{{cite book | last1=Storer | first1=R. James | last2=Ferrante | first2=Antonio | title=Polyamine Protocols | chapter=Radiochemical Assay of Diamine Oxidase | series=Methods in Molecular Biology | publisher=Humana Press | publication-place=New Jersey | volume=79 | date=10 October 1997 | isbn=978-0-89603-448-8 | doi=10.1385/0-89603-448-8:91 | pages=91–96 | pmid=9463822 }}

GABA is also found in plants.{{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 |pages=7879 |year=2015 |pmid=26219411 |pmc=4532832 |doi=10.1038/ncomms8879 |bibcode=2015NatCo...6.7879R}}{{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 |pmc=11107511 |hdl=2440/124330 |s2cid=19475505 |hdl-access=free }} It is the most abundant amino acid in the apoplast of tomatoes.{{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|doi-access= free }} Evidence also suggests a role in cell signalling in plants.{{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}}{{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|bibcode= 2007PlSiB...2..408R }} Recently, a new enzyme technology has been developed to enhance the GABA content of protein-rich seeds such as Andean lupine or tarwi (Lupinus mutabilis) and varieties of quinoa (Chenopodium quinoa) and its relative, cañahua (Chenopodium pallidicaule). {{Cite journal |last1=Ibieta |first1=Gabriela |last2=Ortiz-Sempértegui |first2=Jimena |last3=Peñarrieta |first3=J. Mauricio |last4=Linares-Pastén |first4=Javier A. |date=March 2025 |title=Enhancing the functional value of Andean food plants: Enzymatic production of γ-aminobutyric acid from tarwi, cañihua and quinoa real seeds' proteins |url=https://linkinghub.elsevier.com/retrieve/pii/S0023643825002488 |journal=LWT |language=en |volume=220 |pages=117564 |doi=10.1016/j.lwt.2025.117564|doi-access=free }}

• 3-Aminoisobutyric acid
• 4-aminobutyrate transaminase (GABA-transaminase) deficiency
• GABA analogue
• GABA receptor
• GABA tea
• Giant depolarizing potential
• Spastic diplegia, a GABA deficiency neuromuscular neuropathology
• Spasticity
• Succinic semialdehyde dehydrogenase deficiency
• Taurine

{{Reflist|group=nb}}

{{Reflist}}

{{Commons category|Gamma-Aminobutyric acid}}

• {{cite journal |vauthors=Smart TG, Stephenson FA |title=A half century of γ-aminobutyric acid |journal=Brain Neurosci Adv |volume=3 |pages=2398212819858249 |date=2019 |pmid=32166183 |pmc=7058221 |doi=10.1177/2398212819858249 }}
• {{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
• [https://www.frontiersin.org/articles/10.3389/fnins.2020.00923/full Effects of Oral Gamma-Aminobutyric Acid (GABA) Administration on Stress and Sleep in Humans: A Systematic Review]

{{Non-proteinogenic amino acids}}

{{Neurotransmitters}}

{{GABA receptor modulators}}

{{GABA metabolism and transport modulators}}

{{Authority control}}

{{DEFAULTSORT:Aminobutyric Acid, Gamma-}}

Category:Inhibitory amino acids

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Category:GABA receptor agonists

Category:GABAA receptor positive allosteric modulators

Category:Gamma-Amino acids

Category:Glycine receptor agonists

Category:Biology of obsessive–compulsive disorder

Category:Peripherally selective drugs

Category:Non-proteinogenic amino acids