GABA receptor

File:Cell GABA Receptor.png

{{See also|Ionotropic GABA receptor}}

{{Main|GABAA receptor}}

It has long been recognized that, for neurons that are stimulated by bicuculline and picrotoxin, the fast inhibitory response to GABA is due to direct activation of an anion channel.{{cite journal | vauthors = Kuffler SW, Edwards C | title = Mechanism of gamma aminobutyric acid (GABA) action and its relation to synaptic inhibition | journal = Journal of Neurophysiology | volume = 21 | issue = 6 | pages = 589–610 | date = November 1958 | pmid = 13599049 | doi = 10.1152/jn.1958.21.6.589 | url = http://jn.physiology.org/cgi/citmgr?gca=jn;21/6/589 | url-status = dead | archive-url = https://web.archive.org/web/20040803162301/http://jn.physiology.org/cgi/citmgr?gca=jn | archive-date = 2004-08-03 | url-access = subscription }}{{cite journal | vauthors = Kravitz EA, Kuffler SW, Potter DD | title = Gamma-Aminobutyric Acid and Other Blocking Compounds in Crustacea: III. Their Relative Concentrations in Separated Motor and Inhibitory Axons | journal = Journal of Neurophysiology | volume = 26 | pages = 739–51 | date = September 1963 | issue = 5 | pmid = 14065325 | doi = 10.1152/jn.1963.26.5.739 }}{{cite journal | vauthors = Krnjević K, Schwartz S | title = The action of gamma-aminobutyric acid on cortical neurones | journal = Experimental Brain Research | volume = 3 | issue = 4 | pages = 320–36 | year = 1967 | pmid = 6031164 | doi = 10.1007/BF00237558 | s2cid = 6891616 }}{{cite journal | vauthors = Takeuchi A, Takeuchi N | title = Anion permeability of the inhibitory post-synaptic membrane of the crayfish neuromuscular junction | journal = The Journal of Physiology | volume = 191 | issue = 3 | pages = 575–90 | date = August 1967 | pmid = 6051794 | pmc = 1365493 | doi = 10.1113/jphysiol.1967.sp008269 }}{{cite journal | vauthors = Takeuchi A, Takeuchi N | title = A study of the action of picrotoxin on the inhibitory neuromuscular junction of the crayfish | journal = The Journal of Physiology | volume = 205 | issue = 2 | pages = 377–91 | date = November 1969 | pmid = 5357245 | pmc = 1348609 | doi = 10.1113/jphysiol.1969.sp008972 }} This channel was subsequently termed the GABA_A receptor.{{cite journal | vauthors = Takeuchi A, Onodera K | title = Effect of bicuculline on the GABA receptor of the crayfish neuromuscular junction | journal = Nature | volume = 236 | issue = 63 | pages = 55–6 | date = March 1972 | pmid = 4502428 | doi = 10.1038/236055a0 | s2cid = 12978932 | doi-access = free }} Fast-responding GABA receptors are members of a family of Cys-loop ligand-gated ion channels.{{cite journal | vauthors = Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ | display-authors = 6 | title = International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function | journal = Pharmacological Reviews | volume = 50 | issue = 2 | pages = 291–313 | date = June 1998 | pmid = 9647870 | url = http://pharmrev.aspetjournals.org/cgi/content/full/50/2/291 }}{{cite journal | vauthors = Hevers W, Lüddens H | title = The diversity of GABAA receptors. Pharmacological and electrophysiological properties of GABAA channel subtypes | journal = Molecular Neurobiology | volume = 18 | issue = 1 | pages = 35–86 | date = August 1998 | pmid = 9824848 | doi = 10.1007/BF02741459 | s2cid = 32359279 }}{{cite journal | vauthors = Sieghart W, Sperk G | title = Subunit composition, distribution and function of GABA(A) receptor subtypes | journal = Current Topics in Medicinal Chemistry | volume = 2 | issue = 8 | pages = 795–816 | date = August 2002 | pmid = 12171572 | doi = 10.2174/1568026023393507 }} Members of this superfamily, which includes nicotinic acetylcholine receptors, GABA_A receptors, glycine and 5-HT₃ receptors, possess a characteristic loop formed by a disulfide bond between two cysteine residues.{{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 | doi-access = free }}

In ionotropic GABA_A receptors, binding of GABA molecules to their binding sites in the extracellular part of the receptor triggers opening of a chloride ion-selective pore.{{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 | doi-access = free }} The increased chloride conductance drives the membrane potential towards the reversal potential of the Cl¯ ion which is about –75 mV in neurons, inhibiting the firing of new action potentials. This mechanism is responsible for the sedative effects of GABA_A allosteric agonists. In addition, activation of GABA receptors lead to the so-called shunting inhibition, which reduces the excitability of the cell independent of the changes in membrane potential.

There have been numerous reports of excitatory GABA_A 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{{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 }}{{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 }} or in certain cell populations.{{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 }}{{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 }}{{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 }} After this period of development, a chloride pump is upregulated and inserted into the cell membrane, pumping Cl⁻ 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 inhibitory postsynaptic potentials 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,{{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 }}{{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 }} or that the excitatory GABA was an artefact of neuronal damage.{{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 }} Subsequent studies from originators and proponents of the excitatory GABA theory have questioned these results,{{cite journal | vauthors = Kirmse K, Witte OW, Holthoff K | title = GABA depolarizes immature neocortical neurons in the presence of the ketone body β-hydroxybutyrate | journal = The Journal of Neuroscience | volume = 30 | issue = 47 | pages = 16002–7 | date = November 2010 | pmid = 21106838 | pmc = 6633760 | doi = 10.1523/JNEUROSCI.2534-10.2010 }}{{cite journal | vauthors = Ruusuvuori E, Kirilkin I, Pandya N, Kaila K | title = Spontaneous network events driven by depolarizing GABA action in neonatal hippocampal slices are not attributable to deficient mitochondrial energy metabolism | journal = The Journal of Neuroscience | volume = 30 | issue = 46 | pages = 15638–42 | date = November 2010 | pmid = 21084619 | pmc = 6633692 | doi = 10.1523/JNEUROSCI.3355-10.2010 }}{{cite journal | vauthors = Tyzio R, Allene C, Nardou R, Picardo MA, Yamamoto S, Sivakumaran S, Caiati MD, Rheims S, Minlebaev M, Milh M, Ferré P, Khazipov R, Romette JL, Lorquin J, Cossart R, Khalilov I, Nehlig A, Cherubini E, Ben-Ari Y | display-authors = 6 | title = Depolarizing actions of GABA in immature neurons depend neither on ketone bodies nor on pyruvate | journal = The Journal of Neuroscience | volume = 31 | issue = 1 | pages = 34–45 | date = January 2011 | pmid = 21209187 | pmc = 6622726 | doi = 10.1523/JNEUROSCI.3314-10.2011 }} but the truth remained elusive until the real effects of GABA could be reliably elucidated in intact living brain. Since then, using technology such as in-vivo electrophysiology/imaging and optogenetics, two in-vivo studies have reported the effect of GABA on neonatal brain, and both have shown that GABA is indeed overall inhibitory, with its activation in the developing rodent brain not resulting in network activation,{{cite journal | vauthors = Kirmse K, Kummer M, Kovalchuk Y, Witte OW, Garaschuk O, Holthoff K | title = GABA depolarizes immature neurons and inhibits network activity in the neonatal neocortex in vivo | journal = Nature Communications | volume = 6 | pages = 7750 | date = July 2015 | pmid = 26177896 | doi = 10.1038/ncomms8750 | bibcode = 2015NatCo...6.7750K | doi-access = free }} and instead leading to a decrease of activity.{{cite journal | vauthors = Valeeva G, Tressard T, Mukhtarov M, Baude A, Khazipov R | title = An Optogenetic Approach for Investigation of Excitatory and Inhibitory Network GABA Actions in Mice Expressing Channelrhodopsin-2 in GABAergic Neurons | journal = The Journal of Neuroscience | volume = 36 | issue = 22 | pages = 5961–73 | date = June 2016 | pmid = 27251618 | pmc = 6601813 | doi = 10.1523/JNEUROSCI.3482-15.2016 }}{{cite journal | vauthors = Zilberter M | title = Reality of Inhibitory GABA in Neonatal Brain: Time to Rewrite the Textbooks? | journal = The Journal of Neuroscience | volume = 36 | issue = 40 | pages = 10242–10244 | date = October 2016 | pmid = 27707962 | pmc = 6705588 | doi = 10.1523/JNEUROSCI.2270-16.2016 }}

GABA receptors influence neural function by coordinating with glutamatergic processes.{{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 }}

{{Main|GABAA-rho receptor}}

A subclass of ionotropic GABA receptors, insensitive to typical allosteric modulators of GABA_A receptor channels such as benzodiazepines and barbiturates,{{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 }}{{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 }}{{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 }} was designated GABA_С receptor.{{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 }}{{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 }} Native responses of the GABA_C receptor type occur in retinal bipolar or horizontal cells across vertebrate species.{{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 }}{{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 }}{{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 }}{{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 }}

GABA_С receptors are exclusively composed of ρ (rho) subunits that are related to GABA_A receptor subunits.{{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 }}{{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 }}{{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 }} Although the term "GABA_С receptor" is frequently used, GABA_С may be viewed as a variant within the GABA_A receptor family. Others have argued that the differences between GABA_С and GABA_A receptors are large enough to justify maintaining the distinction between these two subclasses of GABA receptors.{{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 }}{{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 }} However, since GABA_С receptors are closely related in sequence, structure, and function to GABA_A receptors and since other GABA_A receptors besides those containing ρ subunits appear to exhibit GABA_С pharmacology, the Nomenclature Committee of the IUPHAR has recommended that the GABA_С term no longer be used and these ρ receptors should be designated as the ρ subfamily of the GABA_A receptors (GABA_A-ρ).{{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 }}

{{Main|GABAB receptor}}

A slow response to GABA is mediated by GABA_B receptors,{{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 }} originally defined on the basis of pharmacological properties.{{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 }}

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. The most striking discovery was the finding that baclofen (β-parachlorophenyl GABA), a clinically employed muscle relaxant{{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 }}{{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 }} 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.{{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 }} cDNA cloning confirmed that the GABA_B receptor belongs to the family of G-protein coupled receptors.{{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 }} Additional information on GABA_B receptors has been reviewed elsewhere.{{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 }}{{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 }}{{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 }}{{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 }}{{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 }}{{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 }}{{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 }}{{cite book | author = Enna SJ | editor = Möhler H | title = Pharmacology of GABA and Glycine Neurotransmission |series=Handbook of Experimental Pharmacology |volume=150 | publisher = Springer | location = Berlin | year = 2001 | pages = 329–342 | chapter = GABAB receptor signaling pathways | isbn = 3-540-67616-3 }}

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.{{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}} 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,{{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}} 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.{{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}} 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.{{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}} 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,{{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=}} 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.{{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|url-access=subscription}} 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.{{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|url-access=subscription}} A major finding of this study was that functional psychosis should be conceptualized as a scale of phenotypes rather than distinct categories.

• GABA agonist
• GABA antagonist

{{Reflist|2}}

• [http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1276 IUPHAR GPCR Database - GABA_B 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}}

{{G protein-coupled receptors}}

{{Ligand-gated ion channels}}

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Category:Ionotropic receptors

Category:G protein-coupled receptors