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{{Short description|Receptors that respond to gamma-aminobutyric acid}}
[[Image:GABA.png|thumb|[[Gamma-aminobutyric acid]]]]
The '''GABA receptors''' are a class of [[Receptor (biochemistry)|receptors]] that respond to the [[neurotransmitter]] [[gamma-aminobutyric acid]] (GABA), the chief [[inhibitory]] compound in the mature [[vertebrate]] [[central nervous system]]. There are two classes of GABA receptors: [[GABAA receptor|GABA<sub>A</sub>]] and [[GABAB receptor|GABA<sub>B</sub>]]. GABA<sub>A</sub> receptors are [[ligand-gated ion channels]] (also known as [[Ionotropic effect|ionotropic]] receptors); whereas GABA<sub>B</sub> receptors are [[G protein-coupled receptors]], also called [[metabotropic receptors]].
==Ligand-gated ion channels==
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{{Main|GABAA receptor}}
It has long been recognized that,
In ionotropic GABA<sub>A</sub> receptors, binding of GABA molecules to their binding sites in the extracellular part of the receptor triggers opening of a [[chloride ion]]-selective pore.<ref>{{cite journal | vauthors = Phulera S, Zhu H, Yu J, Claxton DP, Yoder N, Yoshioka C, Gouaux E | title = A receptor in complex with GABA | journal = eLife | volume = 7 | pages = e39383 | date = July 2018 | pmid = 30044221 | pmc = 6086659 | doi = 10.7554/eLife.39383 |
There have been numerous reports of excitatory GABA<sub>A</sub> receptors. According to the excitatory GABA theory, this phenomenon is due to increased intracellular concentration of Cl¯ ions either during development of the nervous system<ref name="pmid9364667">{{cite journal |vauthors=Ben-Ari Y, Khazipov R, Leinekugel X, Caillard O, Gaiarsa JL | title = GABAA, NMDA and AMPA receptors: a developmentally regulated 'ménage à trois' | journal = Trends Neurosci. | volume = 20 | issue = 11 | pages = 523–9 |date=November 1997 | pmid = 9364667 | doi = 10.1016/S0166-2236(97)01147-8 | s2cid = 8022055 }}</ref><ref name="pmid10717431">{{cite journal |vauthors=Taketo M, Yoshioka T | title = Developmental change of GABA(A) receptor-mediated current in rat hippocampus | journal = Neuroscience | volume = 96 | issue = 3 | pages = 507–14 | year = 2000 | pmid = 10717431 | doi = 10.1016/S0306-4522(99)00574-6 | s2cid = 22103661 }}</ref> or in certain cell populations.<ref name=Tomiko>{{cite journal |vauthors=Tomiko SA, Taraskevich PS, Douglas WW | title = GABA acts directly on cells of pituitary pars intermedia to alter hormone output | journal = Nature | volume = 301 | issue = 5902 | pages = 706–7 |date=February 1983 | pmid = 6828152 | doi = 10.1038/301706a0 | bibcode = 1983Natur.301..706T | s2cid = 4326183 }}</ref><ref name=Cherubini>{{cite journal |vauthors=Cherubini E, Gaiarsa JL, Ben-Ari Y |title=GABA: an excitatory transmitter in early postnatal life |journal=Trends Neurosci. |volume=14 |issue=12 |pages=515–9 |date=December 1991 | pmid = 1726341 | doi = 10.1016/0166-2236(91)90003-D |s2cid=3971981 }}</ref><ref name=Lamsa>{{cite journal |vauthors=Lamsa K, Taira T | s2cid = 17650510 | title = Use-dependent shift from inhibitory to excitatory GABAA receptor action in SP-O interneurons in the rat hippocampal CA3 area | journal = J. Neurophysiol. | volume=90 |issue = 3 | pages = 1983–95 |date=September 2003 | pmid = 12750426 | doi = 10.1152/jn.00060.2003 }}</ref> After this period of development, a chloride pump is upregulated and inserted into the cell membrane, pumping Cl<sup>−</sup> ions into the extracellular space of the tissue. Further openings via GABA binding to the receptor then produce inhibitory responses. Over-excitation of this receptor induces receptor remodeling and the eventual invagination of the GABA receptor. As a result, further GABA binding becomes inhibited and [[IPSP|inhibitory postsynaptic potential]]s are no longer relevant.
However, the excitatory GABA theory has been questioned as potentially being an artefact of experimental conditions, with most data acquired in in-vitro brain slice experiments susceptible to un-physiological milieu such as deficient energy metabolism and neuronal damage. The controversy arose when a number of studies have shown that GABA in neonatal brain slices becomes inhibitory if glucose in perfusate is supplemented with ketone bodies, pyruvate, or lactate,<ref>{{cite journal | vauthors = Rheims S, Holmgren CD, Chazal G, Mulder J, Harkany T, Zilberter T, Zilberter Y | title = GABA action in immature neocortical neurons directly depends on the availability of ketone bodies | journal = Journal of Neurochemistry | volume = 110 | issue = 4 | pages = 1330–8 | date = August 2009 | pmid = 19558450 | doi = 10.1111/j.1471-4159.2009.06230.x | doi-access = free }}</ref><ref>{{cite journal | vauthors = Holmgren CD, Mukhtarov M, Malkov AE, Popova IY, Bregestovski P, Zilberter Y | title = Energy substrate availability as a determinant of neuronal resting potential, GABA signaling and spontaneous network activity in the neonatal cortex in vitro | journal = Journal of Neurochemistry | volume = 112 | issue = 4 | pages = 900–12 | date = February 2010 | pmid = 19943846 | doi = 10.1111/j.1471-4159.2009.06506.x | doi-access = free }}</ref> or that the excitatory GABA was an artefact of neuronal damage.<ref>{{cite journal | vauthors = Dzhala V, Valeeva G, Glykys J, Khazipov R, Staley K | title = Traumatic alterations in GABA signaling disrupt hippocampal network activity in the developing brain | journal = The Journal of Neuroscience | volume = 32 | issue = 12 | pages = 4017–31 | date = March 2012 | pmid = 22442068 | pmc = 3333790 | doi = 10.1523/JNEUROSCI.5139-11.2012 }}</ref> Subsequent studies from originators and proponents of the excitatory GABA theory have questioned these results,<ref>{{cite journal | vauthors = Kirmse K, Witte OW, Holthoff K | title = GABA depolarizes immature neocortical neurons in the presence of the ketone body
GABA receptors influence neural function by coordinating with glutamatergic processes.<ref>{{cite journal | vauthors = Farahmandfar M, Akbarabadi A, Bakhtazad A, Zarrindast MR | title = Recovery from ketamine-induced amnesia by blockade of GABA-A receptor in the medial prefrontal cortex of mice | journal = Neuroscience | volume = 344 | pages = 48–55 | date = March 2017 | pmid = 26944606 | doi = 10.1016/j.neuroscience.2016.02.056 | s2cid = 24077379 }}</ref>
===GABA<sub>A</sub>-ρ receptor===
{{Main|GABAA-rho receptor}}
A subclass of [[ionotropic]] GABA receptors, insensitive to typical [[Allosteric regulation|allosteric modulators]] of GABA<sub>A</sub> receptor channels such as [[benzodiazepine]]s and [[barbiturate]]s,<ref name="pmid1847747">{{cite journal |vauthors=Sivilotti L, Nistri A | title = GABA receptor mechanisms in the central nervous system | journal = Prog. Neurobiol. | volume = 36 | issue = 1 | pages = 35–92 | year = 1991 | pmid = 1847747 | doi = 10.1016/0301-0082(91)90036-Z | s2cid = 31732465 }}</ref><ref name="pmid8638289">{{cite journal |vauthors=Bormann J, Feigenspan A | title = GABAC receptors | journal = Trends Neurosci. | volume = 18 | issue = 12 | pages = 515–9 |date=December 1995 | pmid = 8638289 | doi = 10.1016/0166-2236(95)98370-E | s2cid = 40853254 }}</ref><ref name="pmid8885697">{{cite journal | author = Johnston GA | title = GABAc receptors: relatively simple transmitter -gated ion channels? | journal = Trends Pharmacol. Sci. | volume = 17 | issue = 9 | pages = 319–23 |date=September 1996 | pmid = 8885697 | doi = 10.1016/0165-6147(96)10038-9 | doi-access = free }}</ref> was designated GABA<sub>С</sub> receptor.<ref name="pmid6097844">{{cite journal | vauthors=Drew CA, Johnston GA, Weatherby RP | title = Bicuculline-insensitive GABA receptors: studies on the binding of (-)-baclofen to rat cerebellar membranes | journal = Neurosci. Lett. | volume = 52 | issue = 3 | pages = 317–21 |date=December 1984 | pmid = 6097844 | doi = 10.1016/0304-3940(84)90181-2 | s2cid = 966075 }}</ref><ref name="pmid11239575">{{cite journal |vauthors=Zhang D, Pan ZH, Awobuluyi M, Lipton SA | title = Structure and function of GABA(C) receptors: a comparison of native versus recombinant receptors | journal = Trends Pharmacol. Sci. | volume = 22 | issue = 3 | pages = 121–32 |date=March 2001 | pmid = 11239575 | doi = 10.1016/S0165-6147(00)01625-4 }}</ref> Native responses of the GABA<sub>C</sub> receptor type occur in [[retina]]l bipolar or horizontal cells across vertebrate species.<ref name="pmid7678450">{{cite journal |vauthors=Feigenspan A, Wässle H, Bormann J | title = Pharmacology of GABA receptor Cl- channels in rat retinal bipolar cells | journal = Nature | volume = 361 | issue = 6408 | pages = 159–62 |date=January 1993 | pmid = 7678450 | doi = 10.1038/361159a0 | bibcode = 1993Natur.361..159F | s2cid = 4347233 }}</ref><ref name="pmid8421521">{{cite journal |vauthors=Qian H, Dowling JE | title = Novel GABA responses from rod-driven retinal horizontal cells | journal = Nature | volume = 361 | issue = 6408 | pages = 162–4 |date=January 1993 | pmid = 8421521 | doi = 10.1038/361162a0 | bibcode = 1993Natur.361..162Q | s2cid = 4320616 }}</ref><ref name="pmid8884747">{{cite journal | author = Lukasiewicz PD | title = GABAC receptors in the vertebrate retina | journal = Mol. Neurobiol. | volume = 12 | issue = 3 | pages = 181–94 |date=June 1996 | pmid = 8884747 | doi = 10.1007/BF02755587 | s2cid = 37167159 }}</ref><ref name="pmid9753143">{{cite journal |vauthors=Wegelius K, Pasternack M, Hiltunen JO, Rivera C, Kaila K, Saarma M, Reeben M | title = Distribution of GABA receptor rho subunit transcripts in the rat brain | journal = Eur. J. Neurosci. | volume = 10 | issue = 1 | pages = 350–7 |date=January 1998 | pmid = 9753143 | doi = 10.1046/j.1460-9568.1998.00023.x | s2cid = 25863134 }}</ref>
GABA<sub>С</sub> receptors are exclusively composed of ρ (rho) subunits that are related to GABA<sub>A</sub> receptor subunits.<ref name="pmid1314944">{{cite journal |vauthors=Shimada S, Cutting G, Uhl GR | title = gamma-Aminobutyric acid A or C receptor? gamma-Aminobutyric acid rho 1 receptor RNA induces bicuculline-, barbiturate-, and benzodiazepine-insensitive gamma-aminobutyric acid responses in Xenopus oocytes | journal = Mol. Pharmacol. | volume = 41 | issue = 4 | pages = 683–7 |date=April 1992 | pmid = 1314944 | url = http://molpharm.aspetjournals.org/cgi/reprint/41/4/683 }}</ref><ref name="pmid8388298">{{cite journal |vauthors=Kusama T, Spivak CE, Whiting P, Dawson VL, Schaeffer JC, Uhl GR | title = Pharmacology of GABA rho 1 and GABA alpha/beta receptors expressed in Xenopus oocytes and COS cells | journal = Br. J. Pharmacol. | volume = 109 | issue = 1 | pages = 200–6 |date=May 1993 | pmid = 8388298 | pmc = 2175610 | doi = 10.1111/j.1476-5381.1993.tb13554.x }}</ref><ref name="pmid8386671">{{cite journal |vauthors=Kusama T, Wang TL, Guggino WB, Cutting GR, Uhl GR | title = GABA rho 2 receptor pharmacological profile: GABA recognition site similarities to rho 1 | journal = Eur. J. Pharmacol. | volume = 245 | issue = 1 | pages = 83–4 |date=March 1993 | pmid = 8386671 | doi = 10.1016/0922-4106(93)90174-8 }}</ref> Although the term "GABA<sub>С</sub> receptor" is frequently used, GABA<sub>С</sub> may be viewed as a variant within the GABA<sub>A</sub> receptor family.<ref name=Barnard/> Others have argued that the differences between GABA<sub>С</sub> and GABA<sub>A</sub> receptors are large enough to justify maintaining the distinction between these two subclasses of GABA receptors.<ref name="pmid10780899">{{cite journal |vauthors=Chebib M, Johnston GA | title = GABA-Activated ligand gated ion channels: medicinal chemistry and molecular biology | journal = J. Med. Chem. | volume = 43 | issue = 8 | pages = 1427–47 |date=April 2000 | pmid = 10780899 | doi = 10.1021/jm9904349 }}</ref><ref name="pmid10637650">{{cite journal | author = Bormann J | title = The 'ABC' of GABA receptors | journal = Trends Pharmacol. Sci. | volume = 21 | issue = 1 | pages = 16–9 |date=January 2000 | pmid = 10637650 | doi = 10.1016/S0165-6147(99)01413-3 }}</ref> However, since GABA<sub>С</sub> receptors are closely related in sequence, structure, and function to GABA<sub>A</sub> receptors and since other GABA<sub>A</sub> receptors besides those containing ρ subunits appear to exhibit GABA<sub>С</sub> pharmacology, the Nomenclature Committee of the [[International Union of Basic and Clinical Pharmacology|IUPHAR]] has recommended that the GABA<sub>С</sub> term no longer be used and these ρ receptors should be designated as the ρ subfamily of the GABA<sub>A</sub> receptors (GABA<sub>A</sub>-ρ).<ref name="pmid18790874">{{cite journal |vauthors=Olsen RW, Sieghart W | title = International Union of Pharmacology. LXX. Subtypes of γ-Aminobutyric AcidA Receptors: Classification on the Basis of Subunit Composition, Pharmacology, and Function. Update | journal = Pharmacological Reviews | volume = 60 | issue = 3 | pages = 243–60 |date=September 2008 | pmid = 18790874 | doi = 10.1124/pr.108.00505 | pmc = 2847512 }}</ref>
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{{Main|GABAB receptor}}
A slow response to GABA is mediated by [[GABA B receptor|GABA<sub>B</sub> receptors]],<ref name="pmid12037141">{{cite journal |vauthors=Bowery NG, Bettler B, Froestl W, Gallagher JP, Marshall F, Raiteri M, Bonner TI, Enna SJ | title = International Union of Pharmacology. XXXIII. Mammalian gamma-aminobutyric acid(B) receptors: structure and function | journal = Pharmacological Reviews | volume = 54 | issue = 2 | pages = 247–64 |date=June 2002 | pmid = 12037141 | doi = 10.1124/pr.54.2.247 | s2cid = 86015084 }}</ref> originally defined on the basis of pharmacological properties.<ref name="pmid6243177">{{cite journal |vauthors=Bowery NG, Hill DR, Hudson AL, Doble A, Middlemiss DN, Shaw J, Turnbull M | title = (-)Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor | journal = Nature | volume = 283 | issue = 5742 | pages = 92–4 |date=January 1980 | pmid = 6243177 | doi = 10.1038/283092a0 | bibcode = 1980Natur.283...92B | s2cid = 4238700 }}</ref>
In studies focused on the control of neurotransmitter release, it was noted that a GABA receptor was responsible for modulating evoked release in a variety of isolated tissue preparations. This ability of GABA to inhibit neurotransmitter release from these preparations was not blocked by bicuculline, was not mimicked by [[isoguvacine]], and was not dependent on Cl¯, all of which are characteristic of the [[GABA A receptor|GABA<sub>A</sub>]] receptor. The most striking discovery was the finding that [[baclofen]] (β-parachlorophenyl GABA), a clinically employed muscle relaxant<ref name="Bein">{{cite book | author = Bein HJ | editor = Birkmayer W | title = Spasticity: A Topical Survey | publisher = Hans Hubert Bern, Switzerland | year = 1972 | chapter = Pharmacological differentiations of muscle relaxants | pages = 76–89 | isbn = 3-456-00390-0 }}</ref><ref name="Keberle">{{cite book |vauthors=Keberle H, Faigle JW | editor = Birkmayer W | title = Spasticity: A Topical Survey | publisher = Hans Hubert Bern, Switzerland | year = 1972 | chapter = Synthesis and structure-activity relationship of the gamma-aminobutyric acid derivatives | pages = 76–89 | isbn = 3-456-00390-0 }}</ref> mimicked, in a [[stereoselective]] manner, the effect of GABA.
Later ligand-binding studies provided direct evidence of binding sites for baclofen on central neuronal membranes.<ref name="pmid6259535">{{cite journal |vauthors=Hill DR, Bowery NG | title = 3H-baclofen and 3H-GABA bind to bicuculline-insensitive GABA B sites in rat brain | journal = Nature | volume = 290 | issue = 5802 | pages = 149–52 |date=March 1981 | pmid = 6259535 | doi = 10.1038/290149a0 | bibcode = 1981Natur.290..149H | s2cid = 4335907 }}</ref> [[cDNA]] cloning confirmed that the GABA<sub>B</sub> receptor belongs to the family of [[G-protein-coupled receptor|G-protein coupled receptors]].<ref name="pmid9069281">{{cite journal |vauthors=Kaupmann K, Huggel K, Heid J, Flor PJ, Bischoff S, Mickel SJ, McMaster G, Angst C, Bittiger H, Froestl W, Bettler B | title = Expression cloning of GABA(B) receptors uncovers similarity to metabotropic glutamate receptors | journal = Nature | volume = 386 | issue = 6622 | pages = 239–46 |date=March 1997 | pmid = 9069281 | doi = 10.1038/386239a0 | bibcode = 1997Natur.386..239K | s2cid = 4345443 }}</ref> Additional information on GABA<sub>B</sub> receptors has been reviewed elsewhere.<ref name="pmid15989503">{{cite journal | author = Enna SJ | title = GABAB receptor agonists and antagonists: pharmacological properties and therapeutic possibilities | journal = Expert Opin Investig Drugs | volume = 6 | issue = 10 | pages = 1319–25 |date=October 1997 | pmid = 15989503 | doi = 10.1517/13543784.6.10.1319 | doi-access = free }}</ref><ref name="isbn0-89603-458-5">{{cite book |author1=Bowery, N. G. |author2=Enna, S. J. | title = The GABA receptors | publisher = Humana Press | location = Totowa, NJ | year = 1997 | isbn = 0-89603-458-5 }}</ref><ref name="pmid9872317">{{cite journal |vauthors=Kaupmann K, Malitschek B, Schuler V, Heid J, Froestl W, Beck P, Mosbacher J, Bischoff S, Kulik A, Shigemoto R, Karschin A, Bettler B | title = GABA(B)-receptor subtypes assemble into functional heteromeric complexes | journal = Nature | volume = 396 | issue = 6712 | pages = 683–7 |date=December 1998 | pmid = 9872317 | doi = 10.1038/25360 | bibcode = 1998Natur.396..683K | s2cid = 4421681 }}</ref><ref name="pmid9844003">{{cite journal |vauthors=Kaupmann K, Schuler V, Mosbacher J, Bischoff S, Bittiger H, Heid J, Froestl W, Leonhard S, Pfaff T, Karschin A, Bettler B | title = Human γ-aminobutyric acid type B receptors are differentially expressed and regulate inwardly rectifying K+ channels | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 25 | pages = 14991–6 |date=December 1998 | pmid = 9844003 | pmc = 24563 | doi = 10.1073/pnas.95.25.14991 | bibcode = 1998PNAS...9514991K | doi-access = free }}</ref><ref name="pmid10498952">{{cite journal |vauthors=Marshall FH, Jones KA, Kaupmann K, Bettler B | title = GABA receptors - the first 7TM heterodimers | journal = Trends Pharmacol. Sci. | volume = 20 | issue = 10 | pages = 396–9 |date=October 1999 | pmid = 10498952 | doi = 10.1016/S0165-6147(99)01383-8 }}</ref><ref name="pmid10917635">{{cite journal |vauthors=Marshall FH, White J, Main M, Green A, Wise A | title = GABA(B) receptors function as heterodimers | journal = Biochem. Soc. Trans. | volume = 27 | issue = 4 | pages = 530–5 |date=August 1999 | pmid = 10917635 | doi = 10.1042/bst0270530 }}</ref><ref name="pmid10604925">{{cite journal |vauthors=Bowery NG, Enna SJ | title = gamma-aminobutyric acid(B) receptors: first of the functional metabotropic heterodimers | journal = J. Pharmacol. Exp. Ther. | volume = 292 | issue = 1 | pages = 2–7 |date=January 2000 | pmid = 10604925 | url = http://jpet.aspetjournals.org/cgi/content/full/292/1/2 }}</ref><ref name="isbn3-540-67616-3">{{cite book | author = Enna SJ | editor = Möhler H | title = Pharmacology of GABA and Glycine Neurotransmission
== GABA receptor gene polymorphisms ==
Two separate genes on two chromosomes control GABA synthesis - glutamate decarboxylase and alpha-ketoglutarate decarboxylase genes - though not much research has been done to explain this polygenic phenomenon.<ref>{{Cite journal|date=2020-01-01|title=GABA synthesis mediated by γ-aminobutanal dehydrogenase in Synechocystis sp. PCC6803 with disrupted glutamate and α-ketoglutarate decarboxylase genes|url=https://www.sciencedirect.com/science/article/abs/pii/S0168945219310623|journal=Plant Science|language=en|volume=290|pages=110287|doi=10.1016/j.plantsci.2019.110287|issn=0168-9452|last1=Kanwal|first1=Simab|last2=Incharoensakdi|first2=Aran|pmid=31779897|s2cid=204162907|url-access=subscription}}</ref> GABA receptor genes have been studied more in depth, and many have hypothesized about the deleterious effects of polymorphisms in these receptor genes. The most common single nucleotide polymorphisms (SNPs) occurring in GABA receptor genes rho 1, 2, and 3 (GABBR1, GABBR2, and GABBR3) have been more recently explored in literature, in addition to the potential effects of these polymorphisms. However, some research has demonstrated that there is evidence that these polymorphisms caused by single base pair variations may be harmful.
It was discovered that the minor allele of a single nucleotide polymorphism at GABBR1 known as rs1186902 is significantly associated with a later age of onset for migraines,<ref>{{Cite journal|title=Gamma-Aminobutyric Acid (Gaba) Receptors Rho (Gabrr) Gene Polymorphisms and Risk for Migraine|journal=Headache: The Journal of Head and Face Pain|year = 2017|doi=10.1111/head.13122|last1 = García-Martín|first1 = Elena|last2 = Martínez|first2 = Carmen|last3 = Serrador|first3 = Mercedes|last4 = Alonso-Navarro|first4 = Hortensia|last5 = Navacerrada|first5 = Francisco|last6 = Esguevillas|first6 = Gara|last7 = García-Albea|first7 = Esteban|last8 = Agúndez|first8 = José A. G.|last9 = Jiménez-Jiménez|first9 = Félix Javier|volume = 57|issue = 7|pages = 1118–1135|pmid = 28699326|s2cid = 12303665}}</ref> but for the other SNPs, no differences were discovered between genetic and allelic variations in the control vs. migraine participants. Similarly, in a study examining SNPs in rho 1, 2, and 3, and their implication in essential tremor, a nervous system disorder, it was discovered that there were no differences in the frequencies of the allelic variants of polymorphisms for control vs. essential tremor participants.<ref>{{Cite journal|title=Gamma-aminobutyric acid (GABA) receptor rho (GABRR) polymorphisms and risk for essential tremor|journal=Journal of Neurology|year = 2011|doi=10.1007/s00415-010-5708-z|last1 = García-Martín|first1 = Elena|last2 = Martínez|first2 = Carmen|last3 = Alonso-Navarro|first3 = Hortensia|last4 = Benito-León|first4 = Julián|last5 = Lorenzo-Betancor|first5 = Oswaldo|last6 = Pastor|first6 = Pau|last7 = Puertas|first7 = Inmaculada|last8 = Rubio|first8 = Lluisa|last9 = López-Alburquerque|first9 = Tomás|last10 = Agúndez|first10 = José A. G.|last11 = Jiménez-Jiménez|first11 = Félix Javier|volume = 258|issue = 2|pages = 203–211|pmid = 20820800|s2cid = 22082250}}</ref> On the other hand, research examining the effect of SNPs in participants with restless leg syndrome found an "association between GABRR3rs832032 polymorphism and the risk for RLS, and a modifier effect of GABRA4 rs2229940 on the age of onset of RLS" - the latter of which is a modifier gene polymorphism.<ref>{{Cite journal|title=Gamma-aminobutyric acid (GABA) receptors genes polymorphisms and risk for restless legs syndrome|journal=The Pharmacogenomics Journal|year = 2018|doi=10.1038/s41397-018-0023-7|last1 = Jiménez-Jiménez|first1 = Félix Javier|last2 = Esguevillas|first2 = Gara|last3 = Alonso-Navarro|first3 = Hortensia|last4 = Zurdo|first4 = Martín|last5 = Turpín-Fenoll|first5 = Laura|last6 = Millán-Pascual|first6 = Jorge|last7 = Adeva-Bartolomé|first7 = Teresa|last8 = Cubo|first8 = Esther|last9 = Navacerrada|first9 = Francisco|last10 = Amo|first10 = Gemma|last11 = Rojo-Sebastián|first11 = Ana|last12 = Rubio|first12 = Lluisa|last13 = Díez-Fairén|first13 = Mónica|last14 = Pastor|first14 = Pau|last15 = Calleja|first15 = Marisol|last16 = Plaza-Nieto|first16 = José Francisco|last17 = Pilo-De-La-Fuente|first17 = Belén|last18 = Arroyo-Solera|first18 = Margarita|last19 = García-Albea|first19 = Esteban|last20 = Agúndez|first20 = José A. G.|last21 = García-Martín|first21 = Elena|volume = 18|issue = 4|pages = 565–577|pmid = 29720720|s2cid = 13756330}}</ref> The most common GABA receptor SNPs do not correlate with deleterious health effects in many cases, but do in a few.
One significant example of a deleterious mutation is the major association between several GABA receptor gene polymorphisms and schizophrenia. Because GABA is integral to the release of inhibitory neurotransmitters which produce a calming effect and play a role in reducing anxiety, stress, and fear, it is not surprising that polymorphisms in these genes result in more consequences relating to mental health than to physical health. Of an analysis on 19 SNPs on various GABA receptor genes, five SNPs in the GABBR2 group were found to be significantly associated with schizophrenia,<ref>{{Cite journal|last1=Lo|first1=W.-S.|last2=Lau|first2=C.-F.|last3=Xuan|first3=Z.|last4=Chan|first4=C.-F.|last5=Feng|first5=G.-Y.|last6=He|first6=L.|last7=Cao|first7=Z.-C.|last8=Liu|first8=H.|last9=Luan|first9=Q.-M.|last10=Xue|first10=H.|date=June 2004|title=Association of SNPs and haplotypes in GABA A receptor β 2 gene with schizophrenia|journal=Molecular Psychiatry|language=en|volume=9|issue=6|pages=603–608|doi=10.1038/sj.mp.4001461|pmid=14699426|s2cid=5567422|issn=1476-5578|doi-access=}}</ref> which produce the unexpected haplotype frequencies not found in the studies mentioned previously.
Several studies have verified association between alcohol use disorder and the rs279858 polymorphism on the GABRA2 gene e, and higher negative alcohol effects scores for individuals who were homozygous at six SNPs.<ref>{{Cite journal|last1=Koulentaki|first1=Mairi|last2=Kouroumalis|first2=Elias|date=2018-06-01|title=GABAA receptor polymorphisms in alcohol use disorder in the GWAS era|url=https://doi.org/10.1007/s00213-018-4918-4|journal=Psychopharmacology|language=en|volume=235|issue=6|pages=1845–1865|doi=10.1007/s00213-018-4918-4|pmid=29721579|s2cid=13744792|issn=1432-2072}}</ref> Furthermore, a study examining polymorphisms in the GABA receptor beta 2 subunit gene found an association with schizophrenia and bipolar disorder, and examined three SNPs and their effects on disease frequency and treatment dosage.<ref>{{Cite journal|last1=Chen|first1=Jianhuan|last2=Tsang|first2=Shui-Ying|last3=Zhao|first3=Cun-You|last4=Pun|first4=Frank W.|last5=Yu|first5=Zhiliang|last6=Mei|first6=Lingling|last7=Lo|first7=Wing-Sze|last8=Fang|first8=Shisong|last9=Liu|first9=Hua|last10=Stöber|first10=Gerald|last11=Xue|first11=Hong|date=2009-12-01|title=GABRB2 in schizophrenia and bipolar disorder: disease association, gene expression and clinical correlations|url=https://portlandpress.com/biochemsoctrans/article/37/6/1415/65028/GABRB2-in-schizophrenia-and-bipolar-disorder|journal=Biochemical Society Transactions|language=en|volume=37|issue=6|pages=1415–1418|doi=10.1042/BST0371415|pmid=19909288|s2cid=10742771 |issn=0300-5127}}</ref> A major finding of this study was that functional psychosis should be conceptualized as a scale of phenotypes rather than distinct categories.
==See also==
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==External links==
*[http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1276 IUPHAR GPCR Database - GABA<sub>B</sub> receptors] {{Webarchive|url=https://web.archive.org/web/20210919011502/https://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1276 |date=2021-09-19 }}
* {{MeshName|GABA+Receptor}}
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