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{{BioPsy}}
   
The '''GABA<sub>A</sub> receptor''' is one of the three [[Ligand-gated ion channel|ligand-gated]] [[ion channel]]s responsible for mediating the effects of Gamma-AminoButyric Acid ([[GABA]]), the major inhibitory [[neurotransmitter]] in the brain.
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{{downsize|title=GABA<sub>A</sub> receptor}}
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[[Image:NAchR_2BG9.png|thumb|right|402px|Structure of the [[nicotinic acetylcholine receptor]] (nAchR: {{PDB|2BG9}}) which is very similar to the GABA<sub>A</sub> receptor.<ref name="pmid18045122">{{cite journal | author = Clayton T, Chen JL, Ernst M, Richter L, Cromer BA, Morton CJ, Ng H, Kaczorowski CC, Helmstetter FJ, Furtmüller R, Ecker G, Parker MW, Sieghart W, Cook JM | title = An updated unified pharmacophore model of the benzodiazepine binding site on gamma-aminobutyric acid(a) receptors: correlation with comparative models | journal = Curr. Med. Chem. | volume = 14 | issue = 26 | pages = 2755–75 | year = 2007 | pmid = 18045122 | doi = | url = http://www.bentham-direct.org/pages/content.php?CMC/2007/00000014/00000026/0003C.SGM | issn = }}</ref><ref name="pmid16877018">{{cite journal | author = Campagna-Slater V, Weaver DF | title = Molecular modelling of the GABAA ion channel protein | journal = J. Mol. Graph. Model. | volume = 25 | issue = 5 | pages = 721–30 | year = 2007 | month = January | pmid = 16877018 | doi = 10.1016/j.jmgm.2006.06.001 | url = }}</ref><ref name="pmid17012619">{{cite journal | author = Sancar F, Ericksen SS, Kucken AM, Teissére JA, Czajkowski C | title = Structural determinants for high-affinity zolpidem binding to GABA-A receptors | journal = Mol. Pharmacol. | volume = 71 | issue = 1 | pages = 38–46 | year = 2007 | month = January | pmid = 17012619 | doi = 10.1124/mol.106.029595 | url = }}</ref> '''Top''': side view of the nAchR imbedded 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).]]
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[[Image:GABAA_receptor_schematic.png|thumb|right|402px|Schematic structure of the GABA<sub>A</sub> receptor. '''Left''': GABA<sub>A</sub> monomeric subunit imbedded 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 C-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.]]
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The '''GABA<sub>A</sub> receptor''' is one of two [[Ligand-gated ion channel|ligand-gated]] [[ion channel]]s responsible for mediating the effects of [[gamma-aminobutyric acid]] (GABA), the major inhibitory [[neurotransmitter]] in the brain. In addition to the GABA binding site, the GABA<sub>A</sub> receptor complex appears to have distinct [[allosteric regulation|allosteric]] binding sites for [[barbiturate]]s, [[ethanol]], [[inhalational anaesthetic|inhaled anaesthetics]], [[furosemide]], [[gamma-Hydroxybutyric acid|GHB]], [[kavalactones]], [[neuroactive steroid]]s, and [[picrotoxin]].<ref name="Johnston">{{cite journal |author=Johnston GAR |title=GABA<sub>A</sub> Receptor Pharmacology|journal= Pharmacology and Therapeutics |volume= 69 |issue= 3 |pages= 173–198 |year= 1996 | doi = 10.1016/0163-7258(95)02043-8|pmid = 8783370}}</ref>
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The GABA<sub>A</sub> receptor protein complex is also the molecular target of the [[benzodiazepine]] (BZ) class of tranquilizer drugs, and hence this complex is sometimes referred to as the '''benzodiazepine receptor''' (BzR). However benzodiazepines do not bind to the same receptor ''site'' on the protein complex as the endogenous ligand, GABA. Since the binding of some BZs is not specific to GABA<sub>A</sub> receptors and some GABA<sub>A</sub> receptors are insensitive to BZs, the [[International Union of Basic and Clinical Pharmacology|IUPHAR]] has recommended that the name benzodiazepine receptor be replaced by '''BZ-sensitive GABA<sub>A</sub> receptor'''.<ref name="pmid9647870">{{cite journal | author = Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ | title = International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acid<sub>A</sub> receptors: classification on the basis of subunit structure and receptor function | journal = Pharmacol. Rev. | volume = 50 | issue = 2 | pages = 291–313 | year = 1998 | month = June | pmid = 9647870 | doi = | url = http://pharmrev.aspetjournals.org/cgi/content/abstract/50/2/291 | issn = }}</ref>
   
 
==Structure and function==
 
==Structure and function==
The receptor is a [[multimeric]] [[transmembrane receptor]] that consists of five subunits arranged around a central [[pore]]. The receptor sits in the [[membrane]] of its [[neuron]] at a [[synapse]]. The [[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]] [[ion]]s (Cl-) to pass down an [[Wiktionary:gradient|electrochemical gradient]]. Because the [reversal potential] for chloride in most neurons is close to the resting [[membrane potential]], activation of GABA<sub>A</sub> receptors tends to stabilize 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 is typically inhibitory, reducing the activity of the neuron. The GABA<sub>A</sub> channel opens quickly and thus contributes to the early part of the [[inhibitory postsynaptic potential]] (IPSP) (Siegel et al., 1999; Chen et al., 2005).
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The receptor is a [[Oligomer|multimeric]] [[transmembrane receptor]] that consists of five subunits arranged around a central [[pore]]. The receptor sits in the [[cell membrane|membrane]] of its [[neuron]] at a [[synapse]]. The [[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]] [[ion]]s (Cl<sup>−</sup>) to pass down an [[membrane potential|electrochemical gradient]]. Because the [[reversal potential]] for chloride in most neurons is close to or more negative than the resting [[membrane potential]], activation of GABA<sub>A</sub> receptors tends to stabilize 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 is typically inhibitory, reducing the activity of the 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">{{cite book | author = Olsen RW, DeLorey TM | authorlink = | editor = Siegel GJ, Agranoff BW, Fisher SK, Albers RW, Uhler MD | others = | title = Basic neurochemistry: molecular, cellular, and medical aspects | edition = Sixth Edition | language = | publisher = Lippincott-Raven | location = Philadelphia | year = 1999 | origyear = | pages = | quote = | isbn = 0-397-51820-X | oclc = | doi = | url = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=bnchm.section.1181 | chapter = Chapter 16: GABA and Glycine }}</ref><ref> 1999. [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=bnchm.section.1181 ''Basic Neurochemistry: Molecular, Cellular and Medical Aspects'', Sixth Edition]. GABA Receptor Physiology and Pharmacology. .</ref><ref name="Chen">{{cite journal |author=Chen K, Li HZ, Ye N, Zhang J, Wang JJ|title=Role of GABA<sub>B</sub> receptors in GABA and baclofen-induced inhibition of adult rat cerebellar interpositus nucleus neurons ''in vitro''|journal= Brain Res Bull |volume= 67 |issue= 4 |pages= 310–8 |year= 2005 |pmid= 16182939 | doi = 10.1016/j.brainresbull.2005.07.004}}</ref>
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The endogenous ligand that binds to the benzodiazepine receptor is [[inosine]].
   
 
===Subunits===
 
===Subunits===
GABA<sub>A</sub> receptors are members of the large "''Cys''-loop" superfamily of evolutionarily related and structurally similar [[ligand-gated ion channel]]s that also includes [[nicotinic acetylcholine receptor]]s, [[glycine receptor]]s, and the 5HT<sub>3</sub> [[serotonin]] 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 (Cossart et al., 2005). There are six types of α subunits, three β's, three γ's, as well as a δ, an ε, a π, a θ, and three ρs (Martin and Dunn, 2002; Sieghart et al., Neurochem Int 1999;34:379–85). Five subunits can combine in different ways to form GABA<sub>A</sub> channels, but the most common type in the brain has two α's, two β's, and a γ (Martin and Dunn, 2002). The receptor binds two GABA molecules (Siegel et al., 1999; Colquhoun and Sivilotti, 2004), somewhere between an α and a β subunit (Martin and Dunn, 2002).
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GABA<sub>A</sub> receptors are members of the large "''Cys''-loop" 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 |author=Cossart R, Bernard C, Ben-Ari Y|title=Multiple facets of GABAergic neurons and synapses: multiple fates of GABA signalling in epilepsies|journal= Trends Neurosci |volume= 28 |issue= 2 |pages= 108–15 |year= 2005 |pmid= 15667934 | doi = 10.1016/j.tins.2004.11.011}}</ref>
   
==Agonists and antagonists==
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In humans, the units are as follows:<ref name="MartinDunn">Martin IL and Dunn SMJ. [http://www.tocris.com/pdfs/gabarev.pdf GABA receptors] A review of GABA and the receptors to which it binds. Tocris Cookson LTD. </ref>
Other ligands (besides GABA) interact with the GABA<sub>A</sub> receptor to activate it (agonists), to inhibit its activation (antagonists) or to increase or decrease its response to an agonist (positive and negative allosteric modulators). Such other ligands include [[benzodiazepine]]s (increase pore opening frequency; often the ingredient of sleep pills and anxiety medications), [[imidazopyridine]]s (newer class of sleep medications), [[barbiturate]]s (increase pore opening duration; used as sedatives), and certain [[steroids]], called [[neuroactive steroid]]s.
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* six types of α subunits ([[GABRA1]], [[GABRA2]], [[GABRA3]], [[GABRA4]], [[GABRA5]], [[GABRA6]])
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* three β's ([[GABRB1]], [[GABRB2]], [[GABRB3]])
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* three γ's ([[GABRG1]], [[GABRG2]], [[GABRG3]])
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* as well as a δ ([[GABRD]]), an ε ([[GABRE]]), a π ([[GABRP]]), and a θ ([[GABRQ]])
   
Among antagonists are picrotoxin (which blocks the channel pore) and bicuculline (which occupies the GABA site and prevents GABA from activating the receptor). The antagonist [[flumazenil]] is used medically to reverse the effects of the benzodiazepines.
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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 |author=Enz R, Cutting GR|title=Molecular composition of GABAC receptors|journal= Vision Res |volume= 38 |issue= 10 |pages= 1431–41 |year= 1998 |pmid= 9667009 | doi = 10.1016/S0042-6989(97)00277-0}}</ref> but rather homooligomerize to form [[GABAC receptor|GABA<sub>C</sub> receptors]].
   
A useful property of the many agonists and some antagonists is that they often have a greater interaction with GABA<sub>A</sub> receptors which contain specific subunits. This allows one to determine which GABA<sub>A</sub> receptor subunit combinations are prevalent in particular brain areas and provides a clue as to which subunit combintations may be responsible for behavioral effects of drugs acting at GABA<sub>A</sub> receptors. Among the behavioral effects of such drugs are relief of anxiety (anxiolysis), muscle relaxation, [[sedation]], [[anticonvulsant|anticonvulsion]], and [[anesthesia]].
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Five subunits can combine in different ways to form GABA<sub>A</sub> channels, but the most common type in the brain is a pentamer comprising two α's, two β's, and a γ <sub>2</sub>β<sub>2</sub>γ).<ref name="MartinDunn"> </ref>
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The receptor binds two GABA molecules,<ref name="Colquhoun">{{cite journal |author=Colquhoun D, Sivilotti LG|title=Function and structure in glycine receptors and some of their relatives|journal= Trends Neurosci |volume= 27 |issue= 6 |pages= 337–44 |year= 2004 |pmid= 15165738 | doi = 10.1016/j.tins.2004.04.010}}</ref> at the interface between an α and a β subunit.<ref name="MartinDunn"> </ref>
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== Pharmacology ==
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Other [[ligand (biochemistry)|ligands]] (besides GABA) interact with the GABA<sub>A</sub> receptor complex to increase chloride conductance ([[agonist]]s), decrease conductance ([[inverse agonist]]s) or to bind to the receptor and have no effect other than to prevent the binding of agonists or inverse agonists ([[receptor antagonist|antagonists]]). Hence ligands for the GABA<sub>A</sub> receptor span a range of effects from full agonism to antagonism to inverse agonism.
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===Agonists===
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Full agonists display a large number of effects including anti-anxiety ([[anxiolytic]]), muscle relaxant, [[sedation]], [[anticonvulsant|anti-convulsion]], and at high enough doses, [[anaesthesia]]. Partial agonists may display a subset of these properties (for example anxiolytic without sedation).
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Such other agonist ligands include
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* [[benzodiazepine]]s (increase pore opening frequency; often the active ingredient of [[sleep pill]]s and [[anxiety medications]])
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* [[nonbenzodiazepine]]s (newer class of sleep / anti-anxiety medications)
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* [[barbiturate]]s (increase pore opening duration; used as [[sedative]]s)
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* [[kavalactones]] (psychoactive compounds found in the roots of the [[kava]] plant)<ref name="Hunter">{{cite journal | author=Hunter, A | title=Kava (Piper methysticum) back in circulation | journal=Australian Centre for Complementary Medicine | volume=25 | issue=7 | year=2006 | pages=529}}</ref>
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* certain [[steroids]], called [[neuroactive steroid]]s<ref name="pmid17531325">{{cite journal | author = Herd MB, Belelli D, Lambert JJ | title = Neurosteroid modulation of synaptic and extrasynaptic GABA<sub>A</sub> receptors | journal = Pharmacology & Therapeutics| volume = 116| issue = | pages = 20| year = 2007 | pmid = 17531325 | doi = 10.1016/j.pharmthera.2007.03.007 }}</ref><ref name="pmid17108970">{{cite journal | author = Hosie AM, Wilkins ME, da Silva HM, Smart TG | title = Endogenous neurosteroids regulate GABA<sub>A</sub> receptors through two discrete transmembrane sites | journal = Nature | volume = 444 | issue = 7118 | pages = 486–9 | year = 2006 | pmid = 17108970 | doi = 10.1038/nature05324 }}</ref><ref name="pmid16984997">{{cite journal | author = Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A | title = Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 39 | pages = 14602–7 | year = 2006 | pmid = 16984997 | doi = 10.1073/pnas.0606544103 }}</ref><ref name="pmid16354918">{{cite journal | author = Akk G, Shu HJ, Wang C, Steinbach JH, Zorumski CF, Covey DF, Mennerick S | title = Neurosteroid access to the GABA<sub>A</sub> receptor | journal = J. Neurosci. | volume = 25 | issue = 50 | pages = 11605–13 | year = 2005 | pmid = 16354918 | doi = 10.1523/JNEUROSCI.4173-05.2005 }}</ref><ref name="pmid15959466">{{cite journal | author = Belelli D, Lambert JJ | title = Neurosteroids: endogenous regulators of the GABA<sub>A</sub> receptor | journal = Nat. Rev. Neurosci. | volume = 6 | issue = 7 | pages = 565–75 | year = 2005 | pmid = 15959466 | doi = 10.1038/nrn1703 }}</ref><ref name="pmid16432684">{{cite journal | author = Pinna G, Costa E, Guidotti A | title = Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake | journal = Psychopharmacology (Berl.) | volume = 186 | issue = 3 | pages = 362–72 | year = 2006 | pmid = 16432684 | doi = 10.1007/s00213-005-0213-2 }}</ref><ref name="pmid15694225">{{cite journal | author = Dubrovsky BO | title = Steroids, neuroactive steroids and neurosteroids in psychopathology | journal = Prog. Neuropsychopharmacol. Biol. Psychiatry | volume = 29 | issue = 2 | pages = 169–92 | year = 2005 | pmid = 15694225 | doi = 10.1016/j.pnpbp.2004.11.001 }}</ref><ref name="pmid11750861">{{cite journal | author = Mellon SH, Griffin LD | title = Neurosteroids: biochemistry and clinical significance | journal = Trends Endocrinol. Metab. | volume = 13 | issue = 1 | pages = 35–43 | year = 2002 | pmid = 11750861 | doi = 10.1016/S1043-2760(01)00503-3 }}</ref><ref name="pmid2160838">{{cite journal | author = Puia G, Santi MR, Vicini S, Pritchett DB, Purdy RH, Paul SM, Seeburg PH, Costa E | title = Neurosteroids act on recombinant human GABA<sub>A</sub> receptors | journal = Neuron | volume = 4 | issue = 5 | pages = 759–65 | year = 1990 | pmid = 2160838 | doi = | issn = }}</ref><ref name="pmid2422758">{{cite journal | author = Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM | title = Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor | journal = Science | volume = 232 | issue = 4753 | pages = 1004–7 | year = 1986 | pmid = 2422758 | doi = 10.1126/science.2422758 }}</ref>
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[[Muscimol]] is an agonist used to distinguish GABA<sub>A</sub> from the [[GABAB receptor|GABA<sub>B</sub> receptor]].
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===Antagonists===
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Among antagonists are
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* [[picrotoxin]] (non-competitive; binds the channel pore, effectively blocking any ions from moving through it)
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* [[bicuculline]] (competitive; transiently occupies the GABA binding site, thus preventing GABA from activating the receptor)
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* [[cicutoxin]] and [[oenanthotoxin]], poisons found in certain Northern Hemisphere plants that grow in boggy soils.
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* [[flumazenil]] which is used medically to reverse excessive effects of the benzodiazepines.
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===Inverse agonists===
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Full inverse agonists such as [[DMCM]] have [[anxiogenic]] and [[Epileptic Seizure|convulsant]] properties, while partial inverse agonists may be useful as aids in memory and learning<ref name="pmid16326923">{{cite journal | author = Dawson GR, Maubach KA, Collinson N, Cobain M, Everitt BJ, MacLeod AM, Choudhury HI, McDonald LM, Pillai G, Rycroft W, Smith AJ, Sternfeld F, Tattersall FD, Wafford KA, Reynolds DS, Seabrook GR, Atack JR | title = An inverse agonist selective for alpha5 subunit-containing GABAA receptors enhances cognition | journal = J. Pharmacol. Exp. Ther. | volume = 316 | issue = 3 | pages = 1335–45 | year = 2006 | month = March | pmid = 16326923 | doi = 10.1124/jpet.105.092320 | url = }}</ref> and as antidotes to GABA agonists. An example of a partial inverse agonist is [[Ro15-4513]].
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===Subtype selective ligands===
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A useful property of the many benzodiazepine receptor ligands is that they may display selective binding to particular subsets of receptors comprising specific subunits. This allows one to determine which GABA<sub>A</sub> receptor subunit combinations are prevalent in particular brain areas and provides a clue as to which subunit combinations may be responsible for behavioral effects of drugs acting at GABA<sub>A</sub> receptors. These selective ligands may have pharmacological advantages in that they may allow dissociation of desired therapeutic affects from undesirable side effects.<ref name="pmid17979718">{{cite journal | author = Da Settimo F, Taliani S, Trincavelli ML, Montali M, Martini C | title = GABA A/Bz receptor subtypes as targets for selective drugs | journal = Curr. Med. Chem. | volume = 14 | issue = 25 | pages = 2680–701 | year = 2007 | pmid = 17979718 | doi = | url = http://www.bentham-direct.org/pages/content.php?CMC/2007/00000014/00000025/0004C.SGM | issn = }}</ref> Few subtype selective ligands have gone into clinical use as yet, but some examples of these compounds which are widely used in scientific research are [[Bretazenil]] (subtype-selective partial agonist), [[Imidazenil]] (partial agonist at some subtypes, weak antagonist at others) and [[QH-II-66|QH-ii-066]] (full agonist highly selective for α<sub>5</sub> subtype).
   
 
==See also==
 
==See also==
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*[[GABA B receptor|GABA<sub>B</sub> receptor]]
 
*[[GABA B receptor|GABA<sub>B</sub> receptor]]
 
*[[GABA C receptor|GABA<sub>C</sub> receptor]]
 
*[[GABA C receptor|GABA<sub>C</sub> receptor]]
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*[[Glycine receptor]]
   
 
==References==
 
==References==
*Chen K., Lia H.Z., Yea N., Zhanga J., and Wang J.J. 2005. Role of GABA<sub>B</sub> receptors in GABA and baclofen-induced inhibition of adult rat cerebellar interpositus nucleus neurons in vitro. ''Brain Research Bulletin'', 67(4), 310-318.
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{{Reflist|2}}
*Colquhoun D. and Sivilotti L.G. 2004. Function and structure in glycine receptors and some of their relatives. ''Trends in Neurosciences'', 27(6), 337-344.
 
*Martin I.L., and Dunn S.M.J. 2002. "GABA Receptors". Tocris Cookson Ltd.
 
*Siegel G.J., Agranoff B.W., Fisher S.K., Albers R.W., and Uhler M.D. 1999. [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=bnchm.section.1181 ''Basic Neurochemistry: Molecular, Cellular and Medical Aspects'', Sixth Edition]. GABA Receptor Physiology and Pharmacology. American Society for Neurochemistry. Lippincott Williams and Wilkins.
 
*Cossart R, Bernard C, Ben-Ari Y. 2005. Multiple facets of GABAergic neurons and synapses: multiple fates of GABA signalling in epilepsies. ''TRENDS in Neurosciences'', 28(2), 108-115
 
   
 
==External links==
 
==External links==
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* {{MeshName|Receptors,+GABA-A}}
*[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=bnchm.section.1181 Basic Neurochemistry: GABA Receptor Physiology and Pharmacology ]
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* {{cite book | author = Olsen RW, DeLorey TM | authorlink = | editor = Siegel GJ, Agranoff BW, Fisher SK, Albers RW, Uhler MD | others = | title = Basic neurochemistry: molecular, cellular, and medical aspects | edition = Sixth Edition | language = | publisher = Lippincott-Raven | location = Philadelphia | year = 1999 | origyear = | pages = | quote = | isbn = 0-397-51820-X | oclc = | doi = | url = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=bnchm.section.1181 | chapter = Chapter 16: GABA and Glycine }}
*[http://www.unifr.ch/biochem/DREYER/Neurotransmitters/gaba.htm Dr. Dreyer's GABA-R webpage (University of Fribourg, Switzerland) ]
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* {{cite book | author = Olsen RW, Betz H | authorlink = | editor = Siegel GJ, Albers RW, Brady S , Price DD | others = | title = Basic Neurochemistry: Molecular, Cellular and Medical Aspects | edition = Seventh Edition | language = | publisher = Academic Press | location = Boston | year = 2005 | origyear = | pages = pages 291-302 | quote = | isbn = 0-12-088397-X | oclc = | doi = | url = | chapter = Chapter 16: GABA and Glycine }}
   
 
[[Category:Transmembrane receptors]]
 
[[Category:Transmembrane receptors]]
   
 
{{Link FA|uk}}
 
{{Link FA|uk}}
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{{Ligand-gated ion channels}}
   
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{{enWP|GABA A receptor}}
 
{{enWP|GABA A receptor}}

Latest revision as of 19:00, July 14, 2008

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The correct title of this article is GABAA receptor. It features superscript or subscript characters that are substituted or omitted because of technical limitations.
File:NAchR 2BG9.png
Structure of the nicotinic acetylcholine receptor (nAchR: PDB 2BG9) which is very similar to the GABAA receptor.[1][2][3] Top: side view of the nAchR imbedded in a cell membrane. Bottom: view of the receptor from the extracellular face of the membrane. The subunits are labeled according to the GABAA 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
Schematic structure of the GABAA receptor. Left: GABAA monomeric subunit imbedded in a lipid bilayer (yellow lines connected to blue spheres). The four transmembrane α-helices (1-4) are depicted as cylinders. The disulfide bond in the C-terminal extracellular domain which is characteristic of the family of cys-loop receptors (which includes the GABAA 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 GABAA receptor is one of two ligand-gated ion channels responsible for mediating the effects of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain. In addition to the GABA binding site, the GABAA receptor complex appears to have distinct allosteric binding sites for barbiturates, ethanol, inhaled anaesthetics, furosemide, GHB, kavalactones, neuroactive steroids, and picrotoxin.[4]

The GABAA receptor protein complex is also the molecular target of the benzodiazepine (BZ) class of tranquilizer drugs, and hence this complex is sometimes referred to as the benzodiazepine receptor (BzR). However benzodiazepines do not bind to the same receptor site on the protein complex as the endogenous ligand, GABA. Since the binding of some BZs is not specific to GABAA receptors and some GABAA receptors are insensitive to BZs, the IUPHAR has recommended that the name benzodiazepine receptor be replaced by BZ-sensitive GABAA receptor.[5]

Structure and functionEdit

The receptor is a multimeric transmembrane receptor that consists of five subunits arranged around a central pore. The receptor sits in the membrane of its neuron at a synapse. The 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 ions (Cl) to pass down an electrochemical gradient. Because the reversal potential for chloride in most neurons is close to or more negative than the resting membrane potential, activation of GABAA receptors tends to stabilize the resting potential, and can make it more difficult for excitatory neurotransmitters to depolarize the neuron and generate an action potential. The net effect is typically inhibitory, reducing the activity of the neuron. The GABAA channel opens quickly and thus contributes to the early part of the inhibitory post-synaptic potential (IPSP).[6][7][8] The endogenous ligand that binds to the benzodiazepine receptor is inosine.

SubunitsEdit

GABAA receptors are members of the large "Cys-loop" super-family of evolutionarily related and structurally similar ligand-gated ion channels that also includes nicotinic acetylcholine receptors, glycine receptors, and the 5HT3 receptor. There are numerous subunit isoforms for the GABAA receptor, which determine the receptor’s agonist affinity, chance of opening, conductance, and other properties.[9]

In humans, the units are as follows:[10]

There are three ρ units (GABRR1, GABRR2, GABRR3), however these do not coassemble with the classical GABAA units listed above,[11] but rather homooligomerize to form GABAC receptors.

Five subunits can combine in different ways to form GABAA channels, but the most common type in the brain is a pentamer comprising two α's, two β's, and a γ (α2β2γ).[10]

The receptor binds two GABA molecules,[12] at the interface between an α and a β subunit.[10]

Pharmacology Edit

Other ligands (besides GABA) interact with the GABAA receptor complex to increase chloride conductance (agonists), decrease conductance (inverse agonists) or to bind to the receptor and have no effect other than to prevent the binding of agonists or inverse agonists (antagonists). Hence ligands for the GABAA receptor span a range of effects from full agonism to antagonism to inverse agonism.

AgonistsEdit

Full agonists display a large number of effects including anti-anxiety (anxiolytic), muscle relaxant, sedation, anti-convulsion, and at high enough doses, anaesthesia. Partial agonists may display a subset of these properties (for example anxiolytic without sedation).

Such other agonist ligands include

Muscimol is an agonist used to distinguish GABAA from the GABAB receptor.

AntagonistsEdit

Among antagonists are

  • picrotoxin (non-competitive; binds the channel pore, effectively blocking any ions from moving through it)
  • bicuculline (competitive; transiently occupies the GABA binding site, thus preventing GABA from activating the receptor)
  • cicutoxin and oenanthotoxin, poisons found in certain Northern Hemisphere plants that grow in boggy soils.
  • flumazenil which is used medically to reverse excessive effects of the benzodiazepines.

Inverse agonistsEdit

Full inverse agonists such as DMCM have anxiogenic and convulsant properties, while partial inverse agonists may be useful as aids in memory and learning[24] and as antidotes to GABA agonists. An example of a partial inverse agonist is Ro15-4513.

Subtype selective ligandsEdit

A useful property of the many benzodiazepine receptor ligands is that they may display selective binding to particular subsets of receptors comprising specific subunits. This allows one to determine which GABAA receptor subunit combinations are prevalent in particular brain areas and provides a clue as to which subunit combinations may be responsible for behavioral effects of drugs acting at GABAA receptors. These selective ligands may have pharmacological advantages in that they may allow dissociation of desired therapeutic affects from undesirable side effects.[25] Few subtype selective ligands have gone into clinical use as yet, but some examples of these compounds which are widely used in scientific research are Bretazenil (subtype-selective partial agonist), Imidazenil (partial agonist at some subtypes, weak antagonist at others) and QH-ii-066 (full agonist highly selective for α5 subtype).

See alsoEdit

ReferencesEdit

  1. Clayton T, Chen JL, Ernst M, Richter L, Cromer BA, Morton CJ, Ng H, Kaczorowski CC, Helmstetter FJ, Furtmüller R, Ecker G, Parker MW, Sieghart W, Cook JM (2007). An updated unified pharmacophore model of the benzodiazepine binding site on gamma-aminobutyric acid(a) receptors: correlation with comparative models. Curr. Med. Chem. 14 (26): 2755–75.
  2. Campagna-Slater V, Weaver DF (January 2007). Molecular modelling of the GABAA ion channel protein. J. Mol. Graph. Model. 25 (5): 721–30.
  3. Sancar F, Ericksen SS, Kucken AM, Teissére JA, Czajkowski C (January 2007). Structural determinants for high-affinity zolpidem binding to GABA-A receptors. Mol. Pharmacol. 71 (1): 38–46.
  4. Johnston GAR (1996). GABAA Receptor Pharmacology. Pharmacology and Therapeutics 69 (3): 173–198.
  5. Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ (June 1998). International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. Pharmacol. Rev. 50 (2): 291–313.
  6. Olsen RW, DeLorey TM (1999). "Chapter 16: GABA and Glycine" Siegel GJ, Agranoff BW, Fisher SK, Albers RW, Uhler MD Basic neurochemistry: molecular, cellular, and medical aspects, Sixth Edition, Philadelphia: Lippincott-Raven.
  7. 1999. Basic Neurochemistry: Molecular, Cellular and Medical Aspects, Sixth Edition. GABA Receptor Physiology and Pharmacology. .
  8. Chen K, Li HZ, Ye N, Zhang J, Wang JJ (2005). Role of GABAB receptors in GABA and baclofen-induced inhibition of adult rat cerebellar interpositus nucleus neurons in vitro. Brain Res Bull 67 (4): 310–8.
  9. Cossart R, Bernard C, Ben-Ari Y (2005). Multiple facets of GABAergic neurons and synapses: multiple fates of GABA signalling in epilepsies. Trends Neurosci 28 (2): 108–15.
  10. 10.0 10.1 10.2 Martin IL and Dunn SMJ. GABA receptors A review of GABA and the receptors to which it binds. Tocris Cookson LTD.
  11. Enz R, Cutting GR (1998). Molecular composition of GABAC receptors. Vision Res 38 (10): 1431–41.
  12. Colquhoun D, Sivilotti LG (2004). Function and structure in glycine receptors and some of their relatives. Trends Neurosci 27 (6): 337–44.
  13. Hunter, A (2006). Kava (Piper methysticum) back in circulation. Australian Centre for Complementary Medicine 25 (7): 529.
  14. Herd MB, Belelli D, Lambert JJ (2007). Neurosteroid modulation of synaptic and extrasynaptic GABAA receptors. Pharmacology & Therapeutics 116: 20.
  15. Hosie AM, Wilkins ME, da Silva HM, Smart TG (2006). Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature 444 (7118): 486–9.
  16. Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A (2006). Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis. Proc. Natl. Acad. Sci. U.S.A. 103 (39): 14602–7.
  17. Akk G, Shu HJ, Wang C, Steinbach JH, Zorumski CF, Covey DF, Mennerick S (2005). Neurosteroid access to the GABAA receptor. J. Neurosci. 25 (50): 11605–13.
  18. Belelli D, Lambert JJ (2005). Neurosteroids: endogenous regulators of the GABAA receptor. Nat. Rev. Neurosci. 6 (7): 565–75.
  19. Pinna G, Costa E, Guidotti A (2006). Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake. Psychopharmacology (Berl.) 186 (3): 362–72.
  20. Dubrovsky BO (2005). Steroids, neuroactive steroids and neurosteroids in psychopathology. Prog. Neuropsychopharmacol. Biol. Psychiatry 29 (2): 169–92.
  21. Mellon SH, Griffin LD (2002). Neurosteroids: biochemistry and clinical significance. Trends Endocrinol. Metab. 13 (1): 35–43.
  22. Puia G, Santi MR, Vicini S, Pritchett DB, Purdy RH, Paul SM, Seeburg PH, Costa E (1990). Neurosteroids act on recombinant human GABAA receptors. Neuron 4 (5): 759–65.
  23. Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM (1986). Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 232 (4753): 1004–7.
  24. Dawson GR, Maubach KA, Collinson N, Cobain M, Everitt BJ, MacLeod AM, Choudhury HI, McDonald LM, Pillai G, Rycroft W, Smith AJ, Sternfeld F, Tattersall FD, Wafford KA, Reynolds DS, Seabrook GR, Atack JR (March 2006). An inverse agonist selective for alpha5 subunit-containing GABAA receptors enhances cognition. J. Pharmacol. Exp. Ther. 316 (3): 1335–45.
  25. Da Settimo F, Taliani S, Trincavelli ML, Montali M, Martini C (2007). GABA A/Bz receptor subtypes as targets for selective drugs. Curr. Med. Chem. 14 (25): 2680–701.

External linksEdit

  • MeSH Receptors,+GABA-A
  • Olsen RW, DeLorey TM (1999). "Chapter 16: GABA and Glycine" Siegel GJ, Agranoff BW, Fisher SK, Albers RW, Uhler MD Basic neurochemistry: molecular, cellular, and medical aspects, Sixth Edition, Philadelphia: Lippincott-Raven.
  • Olsen RW, Betz H (2005). "Chapter 16: GABA and Glycine" Siegel GJ, Albers RW, Brady S , Price DD Basic Neurochemistry: Molecular, Cellular and Medical Aspects, Seventh Edition, pages 291-302, Boston: Academic Press.

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