- GABAA receptor
The GABAA receptor is one of two ligand-gated
ion channels responsible for mediating the effects of gamma-aminobutyric acid(GABA), the major inhibitory neurotransmitterin the brain. In addition to the GABA binding site, the GABAA receptor complex appears to have distinct allosteric binding sites for benzodiazepines, barbiturates, ethanol,cite journal | author = 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 = 211–21 | year = 2007 | month = May | pmid = 17591544 | pmc = 2040048 | doi = 10.1016/j.alcohol.2007.04.011 | url = ] inhaled anaesthetics, furosemide, kavalactones, neuroactive steroids, and picrotoxin.cite journal |author=Johnston GAR |title=GABAA 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]
Target for benzodiazepines
ionotropicGABAA receptor protein complex is also the molecular target of the benzodiazepine(BZ) class of tranquilizer drugs. Benzodiazepines do not bind to the same receptor "site" on the protein complex as the endogenous ligand GABA (whose binding site is located between α- and β-subunits), but bind to distinct benzodiazepine binding sites situated at the interface between the α- and γ-subunits of α- and γ-subunit containing GABAA receptors (see figure to the right).cite journal | author = Sigel E | title = Mapping of the benzodiazepine recognition site on GABAA receptors | journal = Curr Top Med Chem | volume = 2 | issue = 8 | pages = 833–9 | year = 2002 | month = August | pmid = 12171574 | url = | doi = 10.2174/1568026023393444 ] cite journal | author = Akabas MH | title = GABAA receptor structure-function studies: a reexamination in light of new acetylcholine receptor structures | journal = Int. Rev. Neurobiol. | volume = 62 | issue = | pages = 1–43 | year = 2004 | pmid = 15530567 | doi = 10.1016/S0074-7742(04)62001-0 | url = ] Whilst the majority of GABAA receptors (those containing α1-, α2-, α3-, or α5-subunits) are benzodiazepine sensitive there exists a minority of GABAA receptors (α4- or α6-subunit containing) which are insensitive to classical 1,4-benzodiazepines,cite journal | author = Derry JM, Dunn SM, Davies M | title = Identification of a residue in the gamma-aminobutyric acid type A receptor alpha subunit that differentially affects diazepam-sensitive and -insensitive benzodiazepine site binding | journal = J. Neurochem. | volume = 88 | issue = 6 | pages = 1431–8 | year = 2004 | month = March | pmid = 15009644 | doi = 10.1046/j.1471-4159.2003.02264.x | url = | doi_brokendate = 2008-08-02 ] but instead are sensitive to other classes of GABAergic drugs such as the neurosteroids and alcohol. In addition peripheral benzodiazepine receptors exist which are not associated with GABAA receptors. As a result the IUPHAR has recommended that the terms "BZ receptor", "GABA/BZ receptor" and "omega receptor" no longer be used and that the term "benzodiazepine receptor" be replaced with "benzodiazepine site".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 acidA 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 | url = http://pharmrev.aspetjournals.org/cgi/content/abstract/50/2/291 | issn = ]
In order for GABAA receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, where the benzodiazepine binds. Once bound, the benzodiazepine locks the GABAA receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABAA receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarising the membrane. This potentiates the inhibitory effect of the available GABA leading to sedatory and anxiolytic effects.
Different benzodiazepines have different affinities for GABAA receptors made up of different collection of subunits, and this means that their pharmacological profile varies with subtype selectivity. For instance, benzodiazepine receptor ligands with high activity at the α1 and/or α5 tend to be more associated with
sedation, ataxiaand amnesia, whereas those with higher activity at GABAA receptors containing α2 and/or α3 subunits generally have greater anxiolyticactivity. [Atack JR. Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site. "Current Drug Targets. CNS and Neurological Disorders". 2003 Aug;2(4):213-32. PMID 12871032] Anticonvulsanteffects can be produced by agonists acting at any of the GABAA subtypes, but current research in this area is focused mainly on producing α2-selective agonists as anticonvulsants which lack the side effects of older drugs such as sedation and amnesia.
The binding site for benzodiazepines is distinct from the binding site for
barbituratesand GABA on the GABAA receptor, and also produces different effects on binding,cite journal | author = Hanson SM, Czajkowski C | title = Structural mechanisms underlying benzodiazepine modulation of the GABA(A) receptor | journal = J. Neurosci. | volume = 28 | issue = 13 | pages = 3490–9 | year = 2008 | month = March | pmid = 18367615 | doi = 10.1523/JNEUROSCI.5727-07.2008 | url = | issn = ] with the benzodiazepines causing bursts of chloride channel opening to occur more often, while the barbiturates cause the duration of bursts of chloride channel opening to become longer.cite journal | author = Twyman RE, Rogers CJ, Macdonald RL | title = Differential regulation of gamma-aminobutyric acid receptor channels by diazepam and phenobarbital | journal = Ann. Neurol. | volume = 25 | issue = 3 | pages = 213–20 | year = 1989 | month = March | pmid = 2471436 | doi = 10.1002/ana.410250302 | url = | issn = ] Since these are separate modulatory effects, they can both take place at the same time, and so the combination of benzodiazepines with barbiturates is strongly synergistic, and can be dangerous if dosage is not strictly controlled.
Also note that some GABAA agonists such as
muscimoland gaboxadoldo bind to the same site on the GABAA receptor complex as GABA itself, and consequently produce effects which are similar but not identical to those of positive allosteric modulators like benzodiazepines.
tructure and function
The receptor is a multimeric
transmembrane receptorthat consists of five subunits arranged around a central pore. The receptor sits in the membrane of its neuronat a synapse. The ligandGABA is the endogenouscompound that causes this receptor to open; once bound to GABA, the proteinreceptor changes conformation within the membrane, opening the pore in order to allow chloride ions (Cl−) to pass down an electrochemical gradient. Because the reversal potentialfor 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).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 = | url = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=bnchm.section.1181 | chapter = Chapter 16: GABA and Glycine ] cite journal |author=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 Res Bull |volume= 67 |issue= 4 |pages= 310–8 |year= 2005 |pmid= 16182939 | doi = 10.1016/j.brainresbull.2005.07.004] The endogenous ligand that binds to the benzodiazepine receptor is inosine.
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.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]
In humans, the units are as follows: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. ]
* six types of α subunits (
GABRA1, GABRA2, GABRA3, GABRA4, GABRA5, GABRA6)
* three β's (
GABRB1, GABRB2, GABRB3)
* three γ's (
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 GABAA units listed above,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] but rather homooligomerize to form GABAC receptors.
The receptor binds two GABA molecules,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] at the interface between an α and a β subunit. ]
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.
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
benzodiazepines (increase pore opening frequency; often the active ingredient of sleep pills and anxiety medications)
nonbenzodiazepines (newer class of sleep / anti-anxiety medications)
barbiturates (increase pore opening duration; used as sedatives)
kavalactones(psychoactive compounds found in the roots of the kavaplant)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]
steroids, called neuroactive steroids(a) cite journal | author = Herd MB, Belelli D, Lambert JJ | title = Neurosteroid modulation of synaptic and extrasynaptic GABAA receptors | journal = Pharmacology & Therapeutics| volume = 116| issue = | pages = 20| year = 2007 | pmid = 17531325 | doi = 10.1016/j.pharmthera.2007.03.007 ; (b) cite journal | author = Hosie AM, Wilkins ME, da Silva HM, Smart TG | title = Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites | journal = Nature | volume = 444 | issue = 7118 | pages = 486–9 | year = 2006 | pmid = 17108970 | doi = 10.1038/nature05324 ; (c) 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 ; (d) cite journal | author = Akk G, Shu HJ, Wang C, Steinbach JH, Zorumski CF, Covey DF, Mennerick S | title = Neurosteroid access to the GABAA receptor | journal = J. Neurosci. | volume = 25 | issue = 50 | pages = 11605–13 | year = 2005 | pmid = 16354918 | doi = 10.1523/JNEUROSCI.4173-05.2005 ; (e) cite journal | author = Belelli D, Lambert JJ | title = Neurosteroids: endogenous regulators of the GABAA receptor | journal = Nat. Rev. Neurosci. | volume = 6 | issue = 7 | pages = 565–75 | year = 2005 | pmid = 15959466 | doi = 10.1038/nrn1703 ; (f) 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 ; (g) 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 ; (h) 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 ; (i) 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 GABAA receptors | journal = Neuron | volume = 4 | issue = 5 | pages = 759–65 | year = 1990 | pmid = 2160838 | doi = | issn = ; (j) 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 ] Muscimolis an agonist used to distinguish GABAA from the GABAB receptor.
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)
cicutoxinand oenanthotoxin, poisons found in certain Northern Hemisphere plants that grow in boggy soils.
flumazenilwhich is used medically to reverse excessive effects of the benzodiazepines.
Full inverse agonists such as
DMCMhave anxiogenicand convulsant properties, while partial inverse agonists such as Ro15-4513or subtype-selective inverse agonists such as α5IAmay be useful as aids in memory and learningcite 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 = ] and as antidotes to the side effects of GABA agonists.
ubtype selective ligands
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.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 | url = | doi = 10.2174/092986707782023190 ] Few subtype selective ligands have gone into clinical use as yet, with the exception of
zolpidemwhich is reasonably selective for α1, but several more selective compounds are in development such as the α3-selective drug adipiplon. There are many examples of subtype-selective compounds which are widely used in scientific research, including CL-218,872(highly α1-selective agonist), bretazenil(subtype-selective partial agonist), imidazeniland L-838,417(both partial agonists at some subtypes, but weak antagonists at others), QH-ii-066 (full agonist highly selective for α5 subtype) and α5IA(selective inverse agonist for α5 subtype).
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