Functional Area Covered by GABAA RECEPTORS

The subunits of various members of the superfamily be evolutionarily cogitate and all are characterized by a large N-terminal extracellular humans with a disulphide bridge, four transmembrane bowls (TM1, TM2, TM3 and TM4) and a looped intracellular domain betwixt TM3 and TM4 as shown on Figure 1. As such, gamma aminobutyric acidA receptors are isoreceptors, composed of multiple subunits encoded by different genes which respond to the same neurotransmitter and produce the same biophysical response, albeit with different affinities, kinetics and drug sensitivities (1:2). The subunits are named (, (, (, ( and ( according to the degree of sequence homology between them, for example ( subunits portion out 70% homology with each other but only 25% homology with ( subunits. The identification of six (, four (, four (, one ( and ii ( subunits and splicing variants of many of them suggests that these receptors have a diversity of biologic roles and raises the possibility of designing selective drug therapies for the treatment of insomnia, epilepsy and anxiety.

The endure, newspaper and GABA cover version potential of native GABAA subunit combinations and their associated polypepetides has late been investigated using affinity labeling, microsequencing, land site directed mutagenesis and domain special(prenominal) localization. Single point mutations at amino acid Phe64 in the N-terminal extracellular domain of the ( subunit

3. Buhr, A.; Baur, R.; Malherbe, P.; Sigel, E. bakshish mutations of the (1(2(2 (-aminobutyric acidA receptor affecting modulation of the channel by ligands of the benzodiazepine backbone site. Mol. Pharmacol. 48:1080-1084; 1996.

Based on the data presented in the inspection the authors present a comprehensive model of the functional domain of an agonist binding site in transmitter-gated ion channel receptors establish on the (1 subunit of the GABAA receptor (Figure 3).

Comparison of the subunit sequences of GABA and benzodiazepine binding regions and alignment with the sequences of similar regions in subunits of nicotinic acetylcholine receptors and glycine receptors denounce two highly conserved regions beginning at Trp69 and Trp94 which fortune the common primary motif, TXDXFF (Figure 4a). Examination of the secondary structural motifs of these regions reveals that the first base region - which carries a portion of the GABA binding site - is probably an (-helix between two (-pleated sheets, and the second region - which contributes to the benzodiazepine binding site - is a turn preceding a trine (-pleated sheet. This conserved structural motif suggests that they may be orientated parallel to one another (figure 4b). The 25 amino acids between these two regions adopt a turn followed by a short helix of about three turns. Taken as a whole these conserved regions occur as ((( motifs which meet structural units commonly found in proteins of diverse function and cellular environments.

The authors conclude that the co-localization of GABA and benzodiazepine binding domain to a single structural unit could provide an explanation for the allosteric interactions between these two binding sites. The positive and negative actions upon channel exercise could be the result of compounds at the modulatory site influencing the extent or probability of ligand-induced (-helix rotation, with the positive or negative modulators increasing or decreasing the degree, likelihood of rotatio
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