The GABAA receptor is one of two ligand-gated ion channels responsible for mediating the effects of Gamma-Amino Butyric Acid (GABA), the major inhibitory neurotransmitter in the brain. The GABAA receptor is also the molecular target of the benzodiazepine class of tranquilizer drugs, and hence it is also often referred to as the benzodiazepine receptor. In addition to the GABA and benzodiazepine binding sites, the GABAA receptor complex appears to have distinct binding sites for furosemide, neuroactive steroids, picrotoxin, barbiturates, ethanol, kavalactones, GHB, and inhalation anesthetics
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 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).
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).
Agonists, antagonists, and inverse agonists
Other ligands (besides GABA) interact with the GABAA receptor 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, anesthesia. 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)
- imidazopyridines (newer class of sleep medications)
- barbiturates (increase pore opening duration; used as sedatives)
- kavalactones (psychoactive compunds 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)
The antagonist flumazenil is used medically to reverse the effects of the benzodiazepines.
Full inverse agonists have convulsive properties while partial inverse agonists may be useful as aids in memory and learning. An example of a partial inverse agonist is Ro15-4513.
Subtype 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.
- ↑ Johnston GAR (1996). "GABAA Receptor Pharmacology". Pharmacology and Therapeutics 69 (3): 173-198. doi:10.1016/0163-7258(95)02043-8. PMID 8783370.
- ↑ Siegel G.J., Agranoff B.W., Fisher S.K., Albers R.W., and Uhler M.D. 1999. Basic Neurochemistry: Molecular, Cellular and Medical Aspects, Sixth Edition. GABA Receptor Physiology and Pharmacology. American Society for Neurochemistry. Lippincott Williams and Wilkins.
- ↑ 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. doi:10.1016/j.brainresbull.2005.07.004. PMID 16182939.
- ↑ 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. doi:10.1016/j.tins.2004.11.011. PMID 15667934.
- ↑ 5.0 5.1 5.2 Martin IL and Dunn SMJ. GABA receptors A review of GABA and the receptors to which it binds. Tocris Cookson LTD. Accessed through web archive on May 15, 2007.
- ↑ Enz R, Cutting GR (1998). "Molecular composition of GABAC receptors". Vision Res 38 (10): 1431-41. doi:10.1016/S0042-6989(97)00277-0. PMID 9667009.
- ↑ Colquhoun D, Sivilotti LG (2004). "Function and structure in glycine receptors and some of their relatives". Trends Neurosci 27 (6): 337-44. doi:10.1016/j.tins.2004.04.010. PMID 15165738.
- ↑ 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". doi:10.1016/j.pharmthera.2007.03.007. PMID 17531325.
- ↑ 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. doi:10.1038/nature05324. PMID 17108970.
- ↑ 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. doi:10.1073/pnas.0606544103. PMID 16984997.
- ↑ 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. doi:10.1523/JNEUROSCI.4173-05.2005. PMID 16354918.
- ↑ Belelli D, Lambert JJ (2005). "Neurosteroids: endogenous regulators of the GABAA receptor". Nat. Rev. Neurosci. 6 (7): 565-75. doi:10.1038/nrn1703. PMID 15959466.
- ↑ 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. doi:10.1007/s00213-005-0213-2. PMID 16432684.
- ↑ Dubrovsky BO (2005). "Steroids, neuroactive steroids and neurosteroids in psychopathology". Prog. Neuropsychopharmacol. Biol. Psychiatry 29 (2): 169-92. doi:10.1016/j.pnpbp.2004.11.001. PMID 15694225.
- ↑ Mellon SH, Griffin LD (2002). "Neurosteroids: biochemistry and clinical significance". Trends Endocrinol. Metab. 13 (1): 35-43. PMID 11750861.
- ↑ 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. PMID 2160838.
- ↑ 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. PMID 2422758.
- Basic Neurochemistry: GABA Receptor Physiology and Pharmacology
- Dr. Dreyer's GABA-R webpage (University of Fribourg, Switzerland)
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Ion channel, receptor: ligand-gated ion channels
|Cys-loop receptors||5-HT receptor (5-HT3 serotonin receptor (A)) - GABA receptor (GABA A (α1, α2, α3, α5, α6, β1, β2, β3, γ2, ε), GABA C (ρ1)) - Glycine receptor (α1) - Nicotinic acetylcholine receptor (α1, α2, α3, α4, α5, α7, β2, β3, β4, δ, ε, (α4)2(β2)3, (α7)5, Ganglion type, Muscle type)|
|Ionotropic glutamate receptors||AMPA (1, 2, 3, 4) - Kainate (1, 2) - NMDA (1, 2A, 2B, 2C, 2D)|
|ATP-gated channels||Purinergic receptors (P2X (1, 4, 5, 7))|
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