Conclusions on the Subtypes

Within the constraints summarised above, it appears that a considerable number of GABAA receptor subtypes can exist in vivo, more than for any

The Molecular Architecture of GABAA Receptors 93 other of the transmitter-gated channels. Each different combination could in principle generate an individual pharmacology. In the af3rclass, these sub-types can be recognised mainly by the great variation in the responses to dif-ferent "BZlm" drugs, i.e. a very wide range of benzodiazepines and many unrelated structures that are active at a single modulatory site which is a char-acteristic of that sub-class. They range through modulatory agonists, partial agonists and inverse agonists to antagonists, and members can be selected therefrom to discriminate between the af3rcombinations. Those structures are reviewed elsewhere (BARNARD et al. 1998), with a list (Table 4 therein) illus-trating 17 cases of potential GABAA receptor subtypes defined thus. In par-ticular, each change at the a position(s) or the rposition in the combination creates a different pharmacology within the scope of that wide range of modulators.

Where r is replaced by 8, f, 7r or

e,

that series cannot be used (see Sect. E). However, the GABAA receptors have a wealth of other modulatory sites (reviewed in several other chapters in this volume) which could be exploited similarly to recognise SUbtypes. The pharmacology of the receptors containing these alternative subunits is in its infancy, but there are already indi-cations that those subunits introduce differences at such sites on the receptor as those for neurosteroids or for loreclezole (DAVIES et al. 1997; NEELANDS et al. 1999; NEELANDS and MACDONALD 1999).

All of the discriminations discussed here are made in the first instance in recombinant co-expression. In some cases we can seek to relate these to actual native combinations, as recognised from immunopurification results or co-localisations of subunits in situ or differing channel characteristics. In a very few favourable cases at present this may allow us to define functional native subtypes. For each of these particular cases strong evidence exists, based on a concurrence of all three of those approaches (with the co-Iocalisations made at the EM level). Thus, they include the combinations a1{32y2 (BENKE et al.

1994; QUIRK et al. 1994b; BRICKLEY et al. 1996; SOMOGYI et al. 1996; NUSSER et al. 1998), a6{3r2 and a6{38 (CARUNCHO and COSTA 1994; QUIRK et al. 1994b;

SAXENA and MACDONALD 1994; DUCIC et al. 1995; BRICKLEY et al. 1996; JECH-LINGER et al. 1998; NUSSER et al. 1998). Much caution is required in pursuing this: even in those favourable cases the native isoform of {3 or of r2 is often not established and nor is the stoichiometry within the molecule. Major bar-riers to absolute identifications are inherent, first in the special combinatorial system of the GABAAreceptors: many more SUbtypes can in this case (but not for most other receptors) be created in vitro than are likely to occur in vivo.

Other barriers arise from the complexity of the brain circuitry, and from the co-occurrence therein of multiple subtypes of GABA receptors in small regions or within a single neurone. To recognise all of the native GABAA

receptors is a challenge for the long term.

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