Ionotropic GABA receptors are members of the "Cys-loop" superfamily of ligand-gated ion channels (cl-LGIC), so named for a conserved motif in the amino-terminal domain in which a pair of cys-teines forms a disulphide bridge (Simon et al., 2004). Other family members include the nicotinic acetyl-choline receptors, glycine receptors and 5-HT3 receptors. In each case, the receptors are pentameric assemblies of subunits (each with four transmembrane domains; M1-4) that form a central ion channel, which is gated by the binding of a small neurotransmitter molecule (Lester et al., 2004; Peters et al., 2005; Unwin, 2005; Sine and Engel, 2006). This remarkable gating reaction is the key to cl-LGIC function. Somehow, the binding of transmitter molecules to extracellular domains of the receptor triggers an extremely rapid conformational change that propagates through the protein to the transmembrane region and results in opening of the ion channel. In the case of GABAA receptors, two GABA molecules bind at the extracellular interfaces between a and p subunits (see below). Investigations into the molecular basis of this phenomenon have been greatly facilitated by recent models of receptor structure, combining the atomic-scale model of the nicotinic acetylcholine receptor (nAChR) from
Torpedo marmorata electric organ (Unwin, 2005) and the crystallographic structure of the soluble acetylcholine-binding protein (AChBP) from Lymnaea stagnalis (Brejc et al., 2001 Celie et al., 2004). This has allowed earlier studies, in which important ion-pair interactions were identified at the interface of the extracellular binding domain and the channel region (Hu et al., 2003; Kash et al., 2003; Kash et al., 2004), to be extended to a more complete atomic-scale picture of the gating process. This now incorporates translation of movement at the agonist-binding site, through electrostatic interactions within the binding domain-ion channel interface, to the M2 region, causing disruption of hydrophobic interactions within the channel and removal of the barrier to ion flow (Czajkowski, 2005; Lee and Sine, 2005; Lummis et al., 2005; Xiu et al., 2005; Corry, 2006; Sine and Engel, 2006).
The molecular diversity of ionotropic GABA receptors has been reviewed extensively (Barnard et al., 1998; Korpi et al., 2002; Sieghart and Sperk, 2002; Rudolph and Mohler, 2004; Sieghart and Ernst, 2005). In mammals, 19 GABAa receptor subunit genes are grouped into eight families according to their sequence similarity (a1-6, ß1-3, g1-3, 8, e, 0, p and p1-3), with additional variation coming from alternative splicing (notably for a5, ß2, ß3 and g2 subunits (Barnard et al., 1998; Simon et al., 2004)). It is often, and correctly, stated that such subunit diversity predicts enormous heterogeneity of receptor types. Indeed, without any form of constraint, 19 different sub-units could form more than two million unique pentameric permutations. However, basic "rules" of assembly (Kittler et al., 2002; Luscher and Keller, 2004) and a differential distribution of subunit types among brain regions and neuronal populations (Wisden et al., 1992; Fritschy and Mohler, 1995; Pirker et al., 2000) greatly reduce the number of receptor subtypes that exist in the CNS. While some subunits such as the a1 and g2 are ubiquitous, others are much more restricted in their distribution. For example, the a6 subunit is confined to granule cells of the cerebellum and inferior colliculus (Luddens et al., 1990), the e and 0 subunits are found principally in nuclei belonging to various diffuse modulatory systems (choli-nergic, noradrenergic, serotonergic, dopaminergic, histaminergic and peptidergic cell groups (Sinkkonen et al., 2000; Moragues et al., 2002, 2003; Sergeeva et al., 2002, 2005) and the p subunit is present at low levels (if at all) in brain, but is strongly expressed in various other organs, including uterus and breast (Hedblom and Kirkness, 1997; Zafrakas et al., 2006).
In general, combinations of a and ß subunits are sufficient to form functional GABAA receptors. However, the vast majority of native receptors are known to contain a third subunit type. Based, primarily, on data from studies employing subunit-specific antibodies, the most abundant GABAA receptor subtype in brain is formed from a1, ß2 and g2 subunits (McKernan and Whiting, 1996; Sieghart and Sperk, 2002; Whiting, 2003; Benke et al., 2004). Data from quantitative immunoprecipitation (Tretter et al., 1997), fluorescence resonance energy transfer between epitope-tagged subunits (Farrar et al., 1999) and electrophysiology of receptors with concatenated subunits (Baumann et al., 2002; Boileau et al., 2005; Baur et al., 2006) suggest a stoichiometry of two a, two ß and one g subunit. Receptors formed from other a, ß and g combinations (e.g., a2ß3g2 or a3ß3g2) are also widely expressed. Less numerous, though no less significant for the specific neuronal populations in which they are expressed, are receptors in which the g subunit is replaced by a 8 subunit (e.g., a4ß38 or a6ß38). In yet other receptor subtypes, the g subunit can be replaced by the e or p subunits, while the p and 0 subunits may be capable of co-assembling with a, ß and g subunits to form receptors containing representatives from four families (Bonnert et al., 1999; Neelands and Macdonald, 1999; Neelands et al., 1999; Sieghart and Sperk, 2002). Finally, additional variability comes from the fact that individual receptors may contain two different a or ß subunit isoforms (Benke et al., 2004; Minier and Sigel, 2004; Boulineau et al., 2005).
While most subunits assemble as heteromers, the three p subunits form functional homo- or het-eromeric assemblies that have sometimes been classed as GABAC receptors (Bormann, 2000; Che-bib and Johnston, 2000; Zhang et al., 2001), based on their pharmacological similarity to bicuculline-insensitive GABA receptors originally identified in spinal cord (for review, see Johnston, 1996).
Nevertheless, they may be more appropriately considered a sub-class of GABAa receptor subunits (Kaila, 1994; Barnard et al., 1998) and, indeed, they appear capable of forming functional receptors with y2 subunits (Qian and Ripps, 1999; Pan and Qian, 2005) or with both al and y2 subunits (Milligan et al., 2004).
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