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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 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 postsynaptic potential (IPSP) (Siegel et al., 1999; Chen et al., 2005).
GABAA receptors are members of the large "Cys-loop" superfamily of evolutionarily related and structurally similar ligand-gated ion channels that also includes nicotinic acetylcholine receptors, glycine receptors, and the 5HT3 serotonin receptor. There are numerous subunit isoforms for the GABAA 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 GABAA 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).
Agonists and antagonists
Other ligands (besides GABA) interact with the GABAA 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 benzodiazepines (increase pore opening frequency; often the ingredient of sleep pills and anxiety medications), imidazopyridines (newer class of sleep medications), barbiturates (increase pore opening duration; used as sedatives), and certain steroids, called neuroactive steroids.
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.
A useful property of the many agonists and some antagonists is that they often have a greater interaction with GABAA receptors which contain 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 combintations may be responsible for behavioral effects of drugs acting at GABAA receptors. Among the behavioral effects of such drugs are relief of anxiety (anxiolysis), muscle relaxation, sedation, anticonvulsion, and anesthesia.
- Chen K., Lia H.Z., Yea N., Zhanga J., and Wang J.J. 2005. Role of GABAB receptors in GABA and baclofen-induced inhibition of adult rat cerebellar interpositus nucleus neurons in vitro. Brain Research Bulletin, 67(4), 310-318.
- 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. 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
- Basic Neurochemistry: GABA Receptor Physiology and Pharmacology
- Dr. Dreyer's GABA-R webpage (University of Fribourg, Switzerland)
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