GABAa receptor gating by agonist

As for all other ligand-gated channels, GABAA receptors convert chemical messages into electrical signals. In less than a millisecond, the binding of two (tiny) molecules of GABA between the a and p subunits induces a conformational change in the (giant) receptor oligomer that opens the central ion channel (see Baumann et al., 2003). This remarkable process is called "gating". In the opinion of Xiu et al. (2005), ''the gating mechanism for the Cys-loop superfamily is one of the most challenging questions in molecular neuroscience''. The full 2BG9 model of the nAChR suggests ways in which the agonist-binding site couples to the transmembrane region and initiates gating; principles applying to the nAChR are likely to apply, with minor variations, to other members of the superfamily (Unwin, 2005).

The basis for a model of how gating works is that specific ion pairs exert precise control over gating (Kash et al., 2003; Xiu et al., 2005). The membrane-near location of two flexible loops, loop 2 and loop 7 (the Cys-loop) in the crystal structure of the AChBP suggested an involvement in gating of the Cys-loop in the GABAa receptor. Indeed, Kash et al. (2003) using an ''ion pair model'', found by site-directed mutagenesis in the al subunit that optimal gating needs electrostatic interactions between negatively charged residues in loops 2 and 7 (Asp57 and Asp 149) and a positively charged residue in the region linking transmembrane domains 2 and 3 (Lys 279). For the p2 subunit of the GABAA receptor the interaction between an acidic residue in loop 7 (Asp 146) and a basic residue in pre-transmembrane domain-1 (Lys 215) helps couple agonist binding to channel gating (Kash et al., 2004). Studies on other members of the ''Cys-loop'' family found residues at corresponding regions in the nicotinic acetylcholine receptor and the serotonin 5-HT3 receptor as critical coupling elements for gating (Lee and Sine, 2005: Lummis et al., 2005). Nevertheless, building on the results of Kash and colleagues in a detailed and broad examination of electrostatic interactions in the subunits, Xiu et al. (2005) concluded that no specific ion pair interaction in fact influences gating, but instead a cluster of charges is important; specific ion pair interactions are non-essential and it is misleading to focus only on specific residues: ''Receptors have evolved to create a compatible collection of charged residues that allows the receptor to assemble and also facilitates the existence of and interconversions among multiple states'' (Xiu et al., 2005).

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