Editing GABAA receptor (section)

{{Short description|Ionotropic receptor and ligand-gated ion channel}}
{{DISPLAYTITLE:GABA<sub>A</sub> receptor}}
[[File:Fig-GABAA receptor.png|thumb|539x539px|Structure of the [[GABAA receptor positive allosteric modulator|GABA<sub>A</sub>]] receptor (α1β1γ2S: [[Protein Data Bank|PDB]]: [https://www.rcsb.org/structure/6DW1 6DW1]). Top: side view of the GABA<sub>A</sub> receptor embedded in a [[cell membrane]]. Bottom: view of the receptor from the extracellular face of the membrane. The subunits are labeled according to the GABA<sub>A</sub> nomenclature and the approximate locations of the GABA and benzodiazepine (BZ) binding sites are noted (between the α- and β-subunits and between the α- and γ-subunits respectively).]]
[[File:GABAA receptor schematic.png|thumb|right|400px|Schematic structure of the GABA<sub>A</sub> receptor. '''Left''': GABA<sub>A</sub> monomeric subunit embedded in a [[lipid bilayer]] (yellow lines connected to blue spheres). The four [[transmembrane domain|transmembrane]] [[alpha helix|α-helices]] (1–4) are depicted as cylinders. The disulfide bond in the N-terminal extracellular domain which is characteristic of the family of [[cys-loop receptors]] (which includes the GABA<sub>A</sub> receptor) is depicted as a yellow line. '''Right''': Five subunits symmetrically arranged about the central chloride anion conduction pore. The extracellular loops are not depicted for the sake of clarity.]]

The '''GABA<sub>A</sub> receptor''' ('''GABA<sub>A</sub>R''') is an [[ionotropic receptor]] and [[ligand-gated ion channel]]. Its [[endogenous]] [[Ligand (biochemistry)|ligand]] is [[γ-aminobutyric acid]] (GABA), the major inhibitory [[neurotransmitter]] in the [[central nervous system]]. Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS).<ref name="PMID21555068">{{cite journal |vauthors=Luscher B, Fuchs T, Kilpatrick CL |title=GABAA receptor trafficking-mediated plasticity of inhibitory synapses |journal=Neuron |volume=70 |issue=3 |pages=385–409 |date=May 2011 |pmid=21555068 |pmc=3093971 |doi=10.1016/j.neuron.2011.03.024 }}</ref>
Upon opening, the GABA<sub>A</sub> receptor on the [[Chemical synapse|postsynaptic cell]] is selectively permeable to [[Chloride|chloride ions]] ({{chem|Cl|-}}) and, to a lesser extent, [[Bicarbonate|bicarbonate ions]] ({{chem|HCO|3|-}}).<ref>{{Cite book|title=The Oxford handbook of stress, health, and coping|date=2011|publisher=Oxford University Press |last=Folkman |first=Susan.|isbn=978-0-19-537534-3|location=Oxford|oclc=540015689}}</ref><ref>{{cite journal | vauthors = Kaila K, Voipio J | title = Postsynaptic fall in intracellular pH induced by GABA-activated bicarbonate conductance | journal = Nature | volume = 330 | issue = 6144 | pages = 163–5 | date = 18 November 1987 | pmid = 3670401 | doi = 10.1038/330163a0 | s2cid = 4330077 | bibcode = 1987Natur.330..163K }}</ref>

GABA<sub>A</sub>R are members of the ligand-gated ion channel receptor superfamily, which is a chloride channel family with a dozen or more heterotetrametric subtypes and 19 distinct subunits. These subtypes have distinct brain regional and subcellular localization, age-dependent expression, and the ability to undergo plastic alterations in response to experience, including drug exposure.<ref name="PMID29407219">{{cite journal |vauthors=Olsen RW |title=GABAA receptor: Positive and negative allosteric modulators |journal=Neuropharmacology |volume=136 |issue=Pt A |pages=10–22 |date=July 2018 |pmid=29407219 |pmc=6027637 |doi=10.1016/j.neuropharm.2018.01.036 }}</ref>

GABA<sub>A</sub>R is not just the target of agonist depressants and antagonist convulsants, but most GABA<sub>A</sub>R medicines also act at additional (allosteric) binding sites on GABA<sub>A</sub>R proteins. Some sedatives and anxiolytics, such as benzodiazepines and related medicines, act on GABA<sub>A</sub>R subtype-dependent extracellular domain sites. Alcohols and neurosteroids, among other general anesthetics, act at GABA<sub>A</sub>R subunit-interface transmembrane locations. High anesthetic dosages of ethanol act on GABA<sub>A</sub>R subtype-dependent transmembrane domain locations. Ethanol acts at GABA<sub>A</sub>R subtype-dependent extracellular domain locations at low intoxication concentrations. Thus, GABA<sub>A</sub>R subtypes have pharmacologically distinct receptor binding sites for a diverse range of therapeutically significant neuropharmacological drugs.<ref name="PMID29407219" />

Depending on the [[membrane potential]] and the ionic concentration difference, this can result in ionic fluxes across the pore. If the membrane potential is higher than the [[equilibrium potential]] (also known as the reversal potential) for chloride ions, when the receptor is activated {{chem|Cl|-}} will flow into the cell.<ref>{{Cite book|title=Principles of neural science |veditors=Kandel ER, Schwartz JH, Jessell TM, Siegelbaum S, Hudspeth AJ, Mack S |isbn=978-1-283-65624-5 |edition=5th |publisher=McGraw-Hill |oclc=919404585}}</ref> This causes an inhibitory effect on [[neurotransmission]] by diminishing the chance of a successful [[action potential]] occurring at the postsynaptic cell. The reversal potential of the GABA<sub>A</sub>-mediated [[inhibitory postsynaptic potential]] (IPSP) in normal solution is &minus;70&nbsp;mV, contrasting the [[GABAB receptor|GABA<sub>B</sub>]] IPSP (&minus;100&nbsp;mV).

The [[active site]] of the GABA<sub>A</sub> receptor is the binding site for GABA and several drugs such as [[muscimol]], [[gaboxadol]], and [[bicuculline]].<ref name="pmid28528665">{{cite book | vauthors = Chua HC, Chebib M | title = GABAA Receptors and the Diversity in their Structure and Pharmacology | volume = 79 | pages = 1–34 | date = 2017 | pmid = 28528665 | doi = 10.1016/bs.apha.2017.03.003 | series = Advances in Pharmacology | isbn = 978-0-12-810413-2 | chapter = GABA a Receptors and the Diversity in their Structure and Pharmacology | s2cid = 41704867 }}</ref> The protein also contains a number of different [[allosteric|allosteric binding sites]] which modulate the activity of the receptor indirectly. These allosteric sites are the targets of various other drugs, including the [[benzodiazepine]]s, [[nonbenzodiazepine]]s, [[neuroactive steroid]]s, [[barbiturate]]s, [[alcohol (drug)|alcohol]] (ethanol),<ref name="pmid17591544">{{cite journal | vauthors = Santhakumar V, Wallner M, Otis TS | title = Ethanol acts directly on extrasynaptic subtypes of GABAA receptors to increase tonic inhibition | journal = Alcohol | volume = 41 | issue = 3 | pages = 211–221 | date = May 2007 | pmid = 17591544 | pmc = 2040048 | doi = 10.1016/j.alcohol.2007.04.011 }}</ref> [[inhalational anaesthetic|inhaled anaesthetics]], [[kavalactones]], [[cicutoxin]], and [[picrotoxin]], among others.<ref name="Johnston">{{cite journal | vauthors = Johnston GA | title = GABAA receptor pharmacology | journal = Pharmacology & Therapeutics | volume = 69 | issue = 3 | pages = 173–198 | year = 1996 | pmid = 8783370 | doi = 10.1016/0163-7258(95)02043-8 }}</ref>

Binding of GABA to the GABAAR causes the receptor to shift from ordered lipids to clusters of PIP2 in the disordered region of the membrane. The spatial distribution of GABAAR in neurons is regulated by astrocyte derived cholesterol.<ref>{{cite journal |last1=Yuan |first1=Zixuan |last2=Pavel |first2=Mahmud Arif |last3=Hansen |first3=Scott B. |title=GABA and astrocytic cholesterol determine the lipid environment of GABAAR in cultured cortical neurons |journal=Communications Biology |date=22 April 2025 |volume=8 |issue=1 |page=647 |doi=10.1038/s42003-025-08026-7 |pmid=40263458 |pmc=12015214 }}</ref> 

Much like the GABA<sub>A</sub> receptor, the GABA<sub>B</sub> receptor is an obligatory heterodimer consisting of GABA<sub>B1</sub> and GABA<sub>B2</sub> subunits. These subunits include an extracellular Venus Flytrap domain (VFT) and a transmembrane domain containing seven α-helices (7TM domain). These structural components play a vital role in intricately modulating neurotransmission and interactions with drugs. <ref>{{cite journal |vauthors=Evenseth LS, Gabrielsen M, Sylte I |title=The GABAB Receptor-Structure, Ligand Binding and Drug Development |journal=Molecules |volume=25 |issue=13 |date=July 2020 |page=3093 |pmid=32646032 |pmc=7411975 |doi=10.3390/molecules25133093 |doi-access=free }}</ref><!--Olsen RW, Sieghart W-->