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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.
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.
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). 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.
In humans, the units are as follows:
- 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)
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).
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 kava plant)
- certain steroids, called neuroactive steroids
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.
Full inverse agonists such as DMCM have anxiogenic and convulsant properties, while partial inverse agonists may be useful as aids in memory and learning 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. 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).
- ↑ 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.
- ↑ Campagna-Slater V, Weaver DF (January 2007). Molecular modelling of the GABAA ion channel protein. J. Mol. Graph. Model. 25 (5): 721–30.
- ↑ 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.
- ↑ Johnston GAR (1996). GABAA Receptor Pharmacology. Pharmacology and Therapeutics 69 (3): 173–198.
- ↑ 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.
- ↑ 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.
- ↑ 1999. Basic Neurochemistry: Molecular, Cellular and Medical Aspects, Sixth Edition. GABA Receptor Physiology and Pharmacology. .
- ↑ 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.
- ↑ 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.
- ↑ 10.0 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.
- ↑ Enz R, Cutting GR (1998). Molecular composition of GABAC receptors. Vision Res 38 (10): 1431–41.
- ↑ Colquhoun D, Sivilotti LG (2004). Function and structure in glycine receptors and some of their relatives. Trends Neurosci 27 (6): 337–44.
- ↑ Hunter, A (2006). Kava (Piper methysticum) back in circulation. Australian Centre for Complementary Medicine 25 (7): 529.
- ↑ Herd MB, Belelli D, Lambert JJ (2007). Neurosteroid modulation of synaptic and extrasynaptic GABAA receptors. Pharmacology & Therapeutics 116: 20.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Belelli D, Lambert JJ (2005). Neurosteroids: endogenous regulators of the GABAA receptor. Nat. Rev. Neurosci. 6 (7): 565–75.
- ↑ 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.
- ↑ Dubrovsky BO (2005). Steroids, neuroactive steroids and neurosteroids in psychopathology. Prog. Neuropsychopharmacol. Biol. Psychiatry 29 (2): 169–92.
- ↑ Mellon SH, Griffin LD (2002). Neurosteroids: biochemistry and clinical significance. Trends Endocrinol. Metab. 13 (1): 35–43.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- 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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Ion channel, receptor: ligand-gated ion channels
5-HT receptor (5-HT3 serotonin receptor (A)) - GABA receptor (GABA A (α1, α2, α3, α4, α5, α6, β1, β2, β3, γ2, γ3, ε), GABA C (ρ1, ρ2)) - Glycine receptor (α1, α2, β) - Nicotinic acetylcholine receptor (α1, α2, α3, α4, α5, α7, α9, β1, β2, β3, β4, δ, ε, (α4)2(β2)3, (α7)5, Ganglion type, Muscle type)
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