Editing GABAA receptor (section)

==Structure and function==
[[File:GABAA-receptor-protein-example-en.svg|thumb|right|275px|Schematic diagram of a GABA<sub>A</sub> receptor protein ((α1)<sub>2</sub>(β2)<sub>2</sub>(γ2)) which illustrates the five combined subunits that form the protein, the chloride ({{chem|Cl|-}}) ion channel pore, the two GABA active binding sites at the α1 and β2 interfaces, and the benzodiazepine (BZD) allosteric binding site<ref name="pmid22446838">{{cite journal|vauthors=Richter L, de Graaf C, Sieghart W, Varagic Z, Mörzinger M, de Esch IJ, Ecker GF, Ernst M|date=March 2012|title=Diazepam-bound GABAA receptor models identify new benzodiazepine binding-site ligands|journal=Nature Chemical Biology|volume=8|issue=5|pages=455–464|doi=10.1038/nchembio.917|pmc=3368153|pmid=22446838}}</ref>]]
[[File:6x3v GABAA-Rezeptorstruktur.png|thumb|Side view of the [[Electron microscope|EM]] structure of the α1β3γ2 GABAA receptor. GABA and the anaesthetic [[etomidate]] are coloured magenta. Subunits in different colours. One alpha and one beta subunit is hidden. Green chloride ions illustrated in the channel pore.<ref name="pmid32879488">{{cite journal | vauthors = Kim JJ, Gharpure A, Teng J, Zhuang Y, Howard RJ, Zhu S, Noviello CM, Walsh RM, Lindahl E, Hibbs RE | display-authors = 6 | title = Shared structural mechanisms of general anaesthetics and benzodiazepines | journal = Nature | volume = 585 | issue = 7824 | pages = 303–308 | date = September 2020 | pmid = 32879488 | pmc = 7486282 | doi = 10.1038/s41586-020-2654-5 }}</ref>]]
Structural understanding of the GABA<sub>A</sub> receptor was initially based on homology models, obtained using crystal structures of homologous proteins like Acetylcholine binding protein (AChBP) and nicotinic acetylcholine (nACh) receptors as templates.<ref>{{cite journal | vauthors = Ernst M, Bruckner S, Boresch S, Sieghart W | title = Comparative models of GABAA receptor extracellular and transmembrane domains: important insights in pharmacology and function | journal = Molecular Pharmacology | volume = 68 | issue = 5 | pages = 1291–1300 | date = November 2005 | pmid = 16103045 | doi = 10.1124/mol.105.015982 | s2cid = 15678338 | url = http://pdfs.semanticscholar.org/c200/428f6c9e06f04a085de7868e10242f1823ac.pdf | archive-url = https://web.archive.org/web/20190303035531/http://pdfs.semanticscholar.org/c200/428f6c9e06f04a085de7868e10242f1823ac.pdf | url-status = dead | archive-date = 2019-03-03 }}</ref><ref>{{cite journal | vauthors = Vijayan RS, Trivedi N, Roy SN, Bera I, Manoharan P, Payghan PV, Bhattacharyya D, Ghoshal N | title = Modeling the closed and open state conformations of the GABA(A) ion channel--plausible structural insights for channel gating | journal = Journal of Chemical Information and Modeling | volume = 52 | issue = 11 | pages = 2958–2969 | date = November 2012 | pmid = 23116339 | doi = 10.1021/ci300189a }}</ref><ref>{{cite journal | vauthors = Mokrab Y, Bavro V, Mizuguchi K, Todorov NP, Martin IL, Dunn SM, Chan SL, Chau PL | title = Exploring ligand recognition and ion flow in comparative models of the human GABA type A receptor | journal = Journal of Molecular Graphics and Modelling | volume = 26 | issue = 4 | pages = 760–774 | date = November 2007 | doi = 10.1016/j.jmgm.2007.04.012 | pmid = 17544304 | bibcode = 2007JMGM...26..760M }}</ref> The much sought structure of a GABA<sub>A</sub> receptor was finally resolved, with the disclosure of the crystal structure of human β3 homopentameric GABA<sub>A </sub> receptor.<ref>{{cite journal | vauthors = Miller PS, Aricescu AR | title = Crystal structure of a human GABAA receptor | journal = Nature | volume = 512 | issue = 7514 | pages = 270–275 | date = August 2014 | pmid = 24909990 | pmc = 4167603 | doi = 10.1038/nature13293 | bibcode = 2014Natur.512..270M }}</ref>
Whilst this was a major development, the majority of GABA<sub>A</sub> receptors are heteromeric and the structure did not provide any details of the benzodiazepine binding site. This was finally elucidated in 2018 by the publication of a high resolution [[cryo-EM]] structure of rat α1β1γ2S receptor<ref name="pmid30044221" /> and human α1β2γ2 receptor bound with GABA and the neutral benzodiazepine flumazenil.<ref>{{cite journal | vauthors = Zhu S, Noviello CM, Teng J, Walsh RM, Kim JJ, Hibbs RE | title = Structure of a human synaptic GABA<sub>A</sub> receptor | journal = Nature | volume = 559 | issue = 7712 | pages = 67–72 | date = July 2018 | pmid = 29950725 | pmc = 6220708 | doi = 10.1038/s41586-018-0255-3 | bibcode = 2018Natur.559...67Z }}</ref>

GABA<sub>A</sub> receptors are [[pentamer]]ic [[transmembrane receptor]]s which consist of five subunits arranged around a central [[Ion channel pore|pore]]. Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly. The receptor sits in the [[cell membrane|membrane]] of its [[neuron]], usually localized at a [[synapse]], postsynaptically. However, some isoforms may be found extrasynaptically.<ref>{{cite journal | vauthors = Wei W, Zhang N, Peng Z, Houser CR, Mody I | title = Perisynaptic localization of delta subunit-containing GABA(A) receptors and their activation by GABA spillover in the mouse dentate gyrus | journal = The Journal of Neuroscience | volume = 23 | issue = 33 | pages = 10650–61 | date = November 2003 | pmid = 14627650 | pmc = 6740905 | doi = 10.1523/JNEUROSCI.23-33-10650.2003 }}</ref> When [[Synaptic vesicle|vesicles]] of GABA are released presynaptically and activate the GABA receptors at the synapse, this is known as phasic inhibition. However, the GABA escaping from the synaptic cleft can activate receptors on presynaptic terminals or at neighbouring synapses on the same or adjacent neurons (a phenomenon termed 'spillover') in addition to the constant, low GABA concentrations in the extracellular space results in persistent activation of the GABA<sub>A</sub> receptors known as tonic inhibition.<ref>{{cite journal | vauthors = Farrant M, Nusser Z | title = Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors | journal = Nature Reviews. Neuroscience | volume = 6 | issue = 3 | pages = 215–29 | date = March 2005 | pmid = 15738957 | doi = 10.1038/nrn1625 | s2cid = 18552767 }}</ref>

The [[ligand (biochemistry)|ligand]] GABA is the [[endogenous]] compound that causes this receptor to open; once bound to GABA, the [[protein]] receptor changes conformation within the membrane, opening the pore in order to allow [[chloride]] [[anion]]s ({{chem|Cl|-}}) and, to a lesser extent, [[Bicarbonate|bicarbonate ions]] ({{chem|HCO|3|-}}) to pass down their [[membrane potential|electrochemical gradient]]. The binding site to GABA is about 80Å away from the narrowest part of the ion channel. Recent computational studies have suggested an allosteric mechanism whereby GABA binding leads to ion channel opening.<ref>{{cite journal | vauthors = Várnai C, Irwin BW, Payne MC, Csányi G, Chau PL | title = Functional movements of the GABA type A receptor | journal = Physical Chemistry Chemical Physics | volume = 22 | issue = 28 | pages = 16023–16031 | date = July 2020 | pmid = 32633279 | doi = 10.1039/D0CP01128B | bibcode = 2020PCCP...2216023V | doi-access = free }}</ref> Because the [[reversal potential]] for chloride in most mature neurons is close to or more negative than the resting [[membrane potential]], activation of GABA<sub>A</sub> receptors tends to stabilize or hyperpolarise the resting potential, and can make it more difficult for excitatory [[neurotransmitter]]s to [[Depolarization|depolarize]] the neuron and generate an [[action potential]]. The net effect therefore typically inhibitory, reducing the activity of the neuron, although depolarizing currents have been observed in response to GABA in immature neurons in early development. This effect during development is due to a modified {{chem|Cl|-}} gradient wherein the anions leave the cells through the GABA<sub>A</sub> receptors, since their intracellular chlorine concentration is higher than the extracellular.<ref>{{cite journal | vauthors = Ben-Ari Y, Cherubini E, Corradetti R, Gaiarsa JL | title = Giant synaptic potentials in immature rat CA3 hippocampal neurones | journal = The Journal of Physiology | volume = 416 | pages = 303–325 | date = September 1989 | pmid = 2575165 | pmc = 1189216 | doi = 10.1113/jphysiol.1989.sp017762 }}</ref> The difference in extracellular chlorine anion concentration is presumed to be due to the higher activity of chloride transporters, such as [[Na-K-Cl cotransporter|NKCC1]], transporting chloride into cells which are present early in development, whereas, for instance, [[Chloride potassium symporter 5|KCC2]] transports chloride out of cells and is the dominant factor in establishing the chloride gradient later in development. These depolarization events have shown to be key in neuronal development.<ref>{{cite journal | vauthors = Spitzer NC | title = How GABA generates depolarization | journal = The Journal of Physiology | volume = 588 | issue = Pt 5 | pages = 757–758 | date = March 2010 | pmid = 20194137 | pmc = 2834934 | doi = 10.1113/jphysiol.2009.183574 }}</ref> In the mature neuron, the GABA<sub>A</sub> channel opens quickly and thus contributes to the early part of the [[inhibitory post-synaptic potential]] (IPSP).<ref name="isbn0-397-51820-X">{{harvnb|16. GABA and Glycine|1999}}</ref><ref name="Chen">{{cite journal | vauthors = Chen K, Li HZ, Ye N, Zhang J, Wang JJ | title = Role of GABAB receptors in GABA and baclofen-induced inhibition of adult rat cerebellar interpositus nucleus neurons in vitro | journal = Brain Research Bulletin | volume = 67 | issue = 4 | pages = 310–318 | date = October 2005 | pmid = 16182939 | doi = 10.1016/j.brainresbull.2005.07.004 | s2cid = 6433030 }}</ref>
The endogenous ligand that binds to the benzodiazepine site is [[inosine]].<ref>{{cite journal | vauthors = Yarom M, Tang XW, Wu E, Carlson RG, Vander Velde D, Lee X, Wu J | title = Identification of inosine as an endogenous modulator for the benzodiazepine binding site of the GABAA receptors | journal = Journal of Biomedical Science | volume = 5 | issue = 4 | pages = 274–280 | date = 2016-08-01 | pmid = 9691220 | doi = 10.1007/bf02255859 }}</ref>

Proper developmental, neuronal cell-type-specific, and activity-dependent GABAergic transmission control is required for nearly all aspects of CNS function.<ref name="PMID21555068" />

It has been proposed that the GABAergic system is disrupted in numerous neurodevelopmental diseases, including fragile X syndrome, Rett syndrome, and Dravet syndrome, and that it is a crucial potential target for therapeutic intervention.<ref>{{cite journal |vauthors=Braat S, Kooy RF |title=The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders |journal=Neuron |volume=86 |issue=5 |pages=1119–30 |date=June 2015 |pmid=26050032 |doi=10.1016/j.neuron.2015.03.042 }}</ref>

===Subunits===
GABA<sub>A</sub> receptors are members of the large pentameric ligand gated ion channel (previously referred to as "''Cys''-loop" receptors) super-family of evolutionarily related and structurally similar [[ligand-gated ion channel]]s that also includes [[nicotinic acetylcholine receptor]]s, [[glycine receptor]]s, and the [[5-HT3 receptor|5HT<sub>3</sub> receptor]]. There are numerous subunit [[isoform]]s for the GABA<sub>A</sub> receptor, which determine the receptor's agonist affinity, chance of opening, conductance, and other properties.<ref name="Cossart">{{cite journal | vauthors = Cossart R, Bernard C, Ben-Ari Y | title = Multiple facets of GABAergic neurons and synapses: multiple fates of GABA signalling in epilepsies | journal = Trends in Neurosciences | volume = 28 | issue = 2 | pages = 108–115 | date = February 2005 | pmid = 15667934 | doi = 10.1016/j.tins.2004.11.011 | s2cid = 1424286 }}</ref>

In humans, the units are as follows:
* six types of α subunits ([[GABRA1]], [[GABRA2]], [[GABRA3]], [[GABRA4]], [[GABRA5]], [[GABRA6]])
* three βs ([[GABRB1]], [[GABRB2]], [[GABRB3]])
* three γs ([[GABRG1]], [[GABRG2]], [[GABRG3]])
* as well as a δ ([[GABRD]]), an ε ([[GABRE]]), a π ([[GABRP]]), and a θ ([[GABRQ]])

There are three ρ units ([[GABRR1]], [[GABRR2]], [[GABRR3]]); however, these do not coassemble with the classical GABA<sub>A</sub> units listed above,<ref name="Enz">{{cite journal | vauthors = Enz R, Cutting GR | title = Molecular composition of GABAC receptors | journal = Vision Research | volume = 38 | issue = 10 | pages = 1431–1441 | date = May 1998 | pmid = 9667009 | doi = 10.1016/S0042-6989(97)00277-0 | s2cid = 14457042 | doi-access =  }}</ref> but rather homooligomerize to form [[GABAA-rho receptor|GABA<sub>A</sub>-ρ receptors]] (formerly classified as GABA<sub>C</sub> receptors but now this [[nomenclature]] has been deprecated<ref name="pmid18760291">{{cite journal | vauthors = Olsen RW, Sieghart W | title = GABA A receptors: subtypes provide diversity of function and pharmacology | journal = Neuropharmacology | volume = 56 | issue = 1 | pages = 141–148 | date = January 2009 | pmid = 18760291 | pmc = 3525320 | doi = 10.1016/j.neuropharm.2008.07.045 }}</ref>).

=== Combinatorial arrays ===
Given the large number of GABA<sub>A</sub> receptors, a great diversity of final pentameric receptor subtypes is possible. Methods to produce cell-based laboratory access to a greater number of possible GABA<sub>A</sub> receptor subunit combinations allow teasing apart of the contribution of specific receptor subtypes and their physiological and pathophysiological function and role in the CNS and in disease.<ref>{{cite journal | vauthors = Shekdar K, Langer J, Venkatachalan S, Schmid L, Anobile J, Shah P, Lancaster A, Babich O, Dedova O, Sawchuk D | display-authors = 6 | title = Cell engineering method using fluorogenic oligonucleotide signaling probes and flow cytometry | journal = Biotechnology Letters | date = March 2021 | volume = 43 | issue = 5 | pages = 949–958 | pmid = 33683511 | pmc = 7937778 | doi = 10.1007/s10529-021-03101-5 }}</ref>

=== Distribution ===
GABA<sub>A</sub> receptors are responsible for most of the physiological activities of GABA in the central nervous system, and the receptor subtypes vary significantly. Subunit composition can vary widely between regions and subtypes may be associated with specific functions. The minimal requirement to produce a GABA-gated ion channel is the inclusion of an α and a β subunit.<ref>{{cite journal | vauthors = Connolly CN, Krishek BJ, McDonald BJ, Smart TG, Moss SJ | title = Assembly and cell surface expression of heteromeric and homomeric gamma-aminobutyric acid type A receptors | journal = The Journal of Biological Chemistry | volume = 271 | issue = 1 | pages = 89–96 | date = January 1996 | pmid = 8550630 | doi = 10.1074/jbc.271.1.89 | doi-access = free }}</ref> The most common GABA<sub>A</sub> receptor is a pentamer comprising two α's, two β's, and a γ (α<sub>2</sub>β<sub>2</sub>γ). In neurons themselves, the type of GABA<sub>A</sub> receptor subunits and their densities can vary between [[cell bodies]] and [[dendrites]].<ref name="pmid17626281">{{cite journal | vauthors = Lorenzo LE, Russier M, Barbe A, Fritschy JM, Bras H | title = Differential organization of gamma-aminobutyric acid type A and glycine receptors in the somatic and dendritic compartments of rat abducens motoneurons | journal = The Journal of Comparative Neurology | volume = 504 | issue = 2 | pages = 112–126 | date = September 2007 | pmid = 17626281 | doi = 10.1002/cne.21442 | s2cid = 26123520 }}</ref> Benzodiazepines and barbiturates amplify the inhibitory effects mediated by the GABAA receptor.<ref>{{cite journal |vauthors=Macdonald RL, Kelly KM |title=Antiepileptic drug mechanisms of action |journal=Epilepsia |volume=36 |issue= Suppl 2|pages=S2–12 |date=1995 |pmid=8784210 |doi=10.1111/j.1528-1157.1995.tb05996.x |hdl=2027.42/66291 |hdl-access=free }}</ref>
GABA<sub>A</sub> receptors can also be found in other tissues, including [[leydig cells]], [[placenta]], [[immune cells]], [[liver]], [[Epiphyseal plate|bone growth plates]] and several other [[Endocrine system|endocrine tissues]]. Subunit expression varies between 'normal' tissue and [[malignancies]], as GABA<sub>A</sub> receptors can influence [[cell proliferation]].<ref>{{cite thesis |first=A.L. ten |last=Hoeve |title=GABA receptors and the immune system |date=2012 |type= |hdl=20.500.12932/10140 |publisher=Utrecht University |url=https://studenttheses.uu.nl/bitstream/handle/20.500.12932/10140/GABA%20receptors%20and%20the%20immune%20system-012012.pdf?sequence=1}}</ref>
{| class="wikitable mw-collapsible"
|+Distribution of Receptor Types<ref>{{cite journal | vauthors = Mortensen M, Patel B, Smart TG | title = GABA Potency at GABA(A) Receptors Found in Synaptic and Extrasynaptic Zones | journal = Frontiers in Cellular Neuroscience | volume = 6 | pages = 1 | date = January 2011 | pmid = 22319471 | pmc = 3262152 | doi = 10.3389/fncel.2012.00001 | doi-access = free }}</ref>
!Isoform
!Synaptic/Extrasynaptic
!Anatomical location
|-
|α1β3γ2S
|Both
|Widespread
|-
|α2β3γ2S
|Both
|Widespread
|-
|α3β3γ2S
|Both
|[[Thalamic reticular nucleus|Reticular thalamic nucleus]]
|-
|α4β3γ2S
|Both
|Thalamic relay cells
|-
|α5β3γ2S
|Both
|Hippocampal pyramidal cells
|-
|α6β3γ2S
|Both
|Cerebellar granule cells
|-
|α1β2γ2S
|Both
|Widespread, most abundant
|-
|α4β3δ
|Extrasynaptic
|Thalamic relay cells
|-
|α6β3δ
|Extrasynaptic
|Cerebellar granule cells
|-
|α1β2
|Extrasynaptic
|Widespread
|-
|α1β3
|Extrasynaptic
|Thalamus, hypothalamus
|-
|α1β2δ
|Extrasynaptic
|Hippocampus
|-
|α4β2δ
|Extrasynaptic
|Hippocampus, Prefrontal cortex
|-
|α3β3θ
|Extrasynaptic
|Hypothalamus
|-
|α3β3ε
|Extrasynaptic
|Hypothalamus
|}