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Biological: Behavioural genetics · Evolutionary psychology · Neuroanatomy · Neurochemistry · Neuroendocrinology · Neuroscience · Psychoneuroimmunology · Physiological Psychology · Psychopharmacology (Index, Outline)
GABA is the chief inhibitory neurotransmitter in the mammalian brain. Along with glycine--that primarily has effects in the spine, brainstem and retina--it is responsible for the vast majority of all inhibitory neurotransmission in the central nervous system (CNS). Between 20-50% of all central synapses use GABA as their transmitter. The enzyme responsible for the formation of GABA from the amino acid glutamate is glutamic acid decarboxylase (Dawson et al., 2005).
There were once thought to be three types of receptors for GABA in the mammalian CNS, designated A, B, and C. The GABA A and GABA C receptors are GABA-gated chloride ion-conducting channels while the GABA B receptor is a member of the seven transmembrane helix-containing, guanine nucleotide-binding receptor G-protein-coupled receptors. The GABA A and GABA C receptors were initially distinguished by their sensitivity to the ligand bicuculline with the former being antagonized by it while the latter were insensitive. While varieties of the GABA A receptor are found all over the CNS, the GABA C receptors are primarily found in the retina. It has become increasingly clear since the mid-1990s that the GABA A and GABA C receptors are simply variants of the same GABA-gated chloride channel that should be simply denoted by the “GABA A” receptor designation (Barnard et al., 1998).
GABA A receptor structure Edit
This channel was subsequently termed the GABAA receptor. Fast-responding GABA receptors are members of family of Cys-loop ligand-gated ion channels. Members of this superfamily, which includes nicotinic acetylcholine receptors, GABAA and GABAС receptors, glycine and 5-HT3 receptors, possess a characteristic loop formed by a disulphide bond between two cysteine residues.
The GABA A receptor is a member of the Cys-loop ligand-gated ion channel superfamily which also includes the glycine, 5-hydroxytryptamine (5-HT, serotonin), and nicotinic acetylcholine receptors. Receptors of this superfamily consist of pentamers of homologous subunits arranged around a central ion-conducting channel (Cromer et al., 2002). There are 19 different subunit genes —not including alternatively-spliced variants such as the short (S) and long (L) forms of the γ2 subunit—divided into eight subunit classes: β1-3, θ, ρ1-2, δ, π, 1-6, γ1-3, ε (listed according to sequence relatedness). It is presumed that these subunits all arose as a result of gene duplications of an original sequence. Within a class of subunits there is approximately 70% sequence identity, and between subunit classes there is approximately 30% sequence identity (Bateson, 2004).
The majority of GABA A receptor subtypes in the mammalian brain contain at least one α, β, and γ subunit (Farrar et al., 1999). Most GABA A receptors consist of assemblies of these three subunit classes. The most abundantly expressed isoform of the GABA A receptor in the mammalian brain is composed of α1, β2, and γ2. The likely stoichiometry is two α , two β and one γ subunit arranged around the ion channel anti-clockwise γ-β-α-β-α as seen from the synaptic cleft (McKernan & Whiting, 1996; Chou, 2004; Farrant & Nusser, 2005).
Each subunit has a common structure consisting of a large amino-terminal portion, four transmembrane helices—designated transmembrane (TM) one to four, and a short, cytoplasmic loop toward the carboxy-terminus that is composed of the loop extending between TM3 and TM4. The receptor subunits are arranged pseudo-symmetrically so that the TM2 helix of each subunit lines the central pore (Bateson, 2004). Recent models of the structure of the GABA A receptor have been based on the crystal structure of the related acetylcholine binding protein (Chou, 2004).
Ligand binding to the GABA A receptor Edit
GABA binding (to the “GABA site”) activates the GABA A receptor, allowing chloride ions to flow through the central pore and hyperpolarize the neuron, decreasing the probability that it will propagate an action potential. In this activity, the GABA A receptor does not differ from any other ligand-gated ion channels. However, among neurotransmitter receptors, GABA A receptors are unique in the number of ligands that allosterically modulate receptor function (Olsen et al., 2004).
GABA A receptors can exist in at least three different conformations: open, closed, and desensitized (Sigel, 2002). Up to 14 different ligand binding sites have been proposed to account for the modulation of GABA (Tsang & Hue, 2004). Binding to the receptor can alter the conformation in such a way as to enhance or diminish the chloride flux in response to GABA binding. Some anesthetics (etomidate, pentobarbitone) both enhance chloride flow in response to GABA binding as well as activating it directly in the absence of GABA. Other ligands, cage convulsants of the picrotoxin type, bind within the central pore, occluding the channel and preventing chloride flow no matter what (other) ligand subsequently binds. Some of these compounds have seen commercial use as pesticides.
Possession of a γ subunit and a particular type of α subunit (1, 2, 3, or 5) is required to confer sensitivity to the class of compounds known as benzodiazepines (an example of which is diazepam—brand name Valium®). Of course, GABA A receptors of these subtypes are overwhelmingly numerically dominant in the CNS. Classical benzodiazepines do not directly open the ion channel, rather they allosterically modify the GABA A receptor upon binding, potentiating the effect of GABA binding when there is a submaximal concentration of GABA present and thereby increasing hyperpolarizing responses and neuronal inhibition. Benzodiazepines produce systemic effects that include sedation, amnesia, muscle relaxation, and anxiolysis (Krogsgaard-Larsen et al., 2002). They were the most widely prescribed class of drugs during the 1970s and, as a group, have one of the largest therapeutic indexes. Although the site is called the benzodiazepine site, drugs of other types can also bind and allosterically modify the receptor at that site. These include drugs with β-carboline, imidazopyridine, and triazolopyridazine structures (Sigel, 2002).
See also Edit
Bernard EA, P Skolnick, RW Olsen, H Mohler, W Sieghart, G Biggio, C Braestrup, AN Bateson, SZ Langer (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: 291-313.
Bateson AN (2004) The benzodiazepine site of the GABA A receptor: an old target with new potential? Sleep Med 5 Suppl 1: S9-15
Chou KC (2004) Modelling extracellular domains of GABA-A receptors: subtypes 1, 2, 3, and 5 Biochem Biophys Res Commun 316: 636-642.
Cromer BA, CJ Morton, MW Parker (2002) Anxiety over GABA(A) receptor structure relieved by AChBP Trends Biochem Sci 27: 280-287.
Dawson GR, N Collison, JR Atack (2005) Development of subtype selective GABAA modulators CNS Spectr 10: 21-27.
Farrant M & Z Nusser (2005) Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors Nat Rev Neurosci 6: 215-229.
Farrar SJ, PJ Whiting, TP Bonnert, RM McKernan (1999) Stoichiometry of ligand-gated ion channel determined by fluorescence energy transfer J Biol Chem 274: 10100-10104.
Krogsgaard-Larsen P, B Frolund, T Liljefors (2002) Specific GABA(A) agonists and partial agonists Chem Rec 2: 419-430.
McKernan RM & PJ Whiting (1996) Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci 19: 139-143.
Olsen RW, CS CHang, G Li, HJ Hanchar, M Wallner (2004) Fishing for allosteric sites on GABA(A) receptors Biochem Pharmacol 68: 1675-1684.
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