Homology modeling of the extracellular as well as the transmembrane domain of the GABAA receptor was based on the 4 Ǻ structure of the nAChR (Unwin, 2003), and indicated that GABAA receptors contain additional cavities in the transmembrane domain in addition to those found extracellularly (Ernst et al., 2005). One set of putative pockets is actually an extension of the extracellular pockets into the lipid bilayer of the transmembrane domain. The extracellular and transmembrane intersubunit pockets, however, are not necessarily connected with each other and could also represent completely separate entities. Another type of cavity is found contained inside each of the subunits surrounded by the four helices that make up the transmembrane domain. These multiple cavities are probably needed for conformational changes of the receptors, but could also serve as drug binding sites. Binding of drugs into any one of these sites could either stabilize or induce conformational changes of the receptor and thus, enhance or reduce GABA-induced chloride flux. These multiple binding sites at a single receptor subtype, thus, could explain the extremely complex pharmacology of GABAA receptors (Ernst et al., 2005).
