GabaA subunits

The diversity of the GABAa subunits (Figure 3.2d) is reflected in a very complex pharmacology. Expression of the subunits in heterologous systems shows that the combinations a, (3, and y can yield functional receptors, indicating that the limitation in subunit combination is defined by expression levels and most likely cell-dependent assembly mechanisms also. The pj to p3 subunits mainly co-assemble with each other to form the GABAC receptors. 

Pyrazolo[l,5-a]pyrimidine, the central scaffold in zaleplon, is present in 5, 6 and 7. Compound 5 inhibits the binding of tritiated benzodiazepine in synaptosomal fractions from rat cortex [20] and 6 and 7 inhibit the al GABAa subunit with K, — 53 nM and 17nM, respectively, and showed sedative-hypnotic action following i.p. administration to mice (<90% inhibition of motor activity)... 

GABAa receptors that contain the al, a2, a3, and a5 subunits in combination with (3 and y subunits can bind classical benzodiazepines, e.g., diazepam, whereas GABAa receptors that contain the a4 and a6 subunits do not bind classical benzodiazepines. Essentially, all benzodiazepines that are currently in clinical use bind indiscriminately to GABAa receptors that contain the... 

In an attempt to visualize the site of action of ethanol, tryptophan mutation at position S270, TM2 and TM3 domains of the GABAa a2 subunit were modeled as antiparallel a-helices. The model showed that the region between S270 TM2 and TM3 contains a small cavity that may not be filled by side chains of adjoining helices. In contrast, the model of the S270W mutation demonstrated that the side chain of tryptophan completely occupied this cavity, which could eliminate occupation of the putative cavity by ethanol. 

These findings were unexpected because previous studies had demonstrated that the y2 subunit is required for potentiation of GABAa receptor function by low concentrations of ethanol [2]. The y2 subunit gene is located within a definitely mapped quantitative trait locus (QTL) for acute alcohol withdrawal on mouse chromosome 11 [1]. Allelic variation was genetically... 

Neurosteroids prolong the mean open time of recombinant GABAa receptor channels. Whereas, at least in recombinant systems, the identity of the a and (3 subunits has little or no effect on neurosteroid action, substitution of the y subunit by a 8 subunit suppresses the GABA-modulatory activity of the neurosteroids. 

Mice lacking the 8 subunit, which is mainly expressed in cerebellum and thalamus, display an attenuation of ssatrighting reflex time following the administration of the neurosteroids, alphaxalone and pregnanolone, while the responses to propofol, etomindate, ketamine and the benzodiazepine midazolam were unaffected. This demonstrates the role of GABAa receptors containing the 8 subunit for neurosteroid action. 

Fritschy J-M, Mohler H (1995) GABAA-receptor heterogeneity in the adult rat brain differential regional and cellular distribution of seven major subunits. J Comp Neurol 14 154-94... 

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