GABAA/benzodiazepine receptor complex

The GABAA/Benzodiazepine Receptor Complex. The GABAa receptor (125-127) is a transmembrane protein belonging to the superfamily of ligand gated ion channels (128). The receptor consists of five subunits ar-... 

Figure 6.1 GABAA-benzodiazepine receptor complex showing subunits and binding sites of ligands (binding sites for GABA and BDZ shown O).

Baude A, Sequier J-M, McKernan RM, Olivier KR, Somogyi P (1992) Differential subcellular distribution of the a6 subunit versus the al and /S2/3 subunits of the GABAA/benzodiazepine receptor complex in granule cells of the cerebellar cortex. Neuroscience, 51, 739-748. 

Fig. 22.17. Ligand interaction with the v-aminobutyric acidA (GABAA)/benzodiazepine receptor complex.

Bassett, M.L., Mullen, K.D., Skolnick, R, and Jones, E.A. 1987. Amelioration of hepatic encephalopathy by pharmacologic antagonism of the GABAA-benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure. Gastroenterology 93 1069-1077. 

Binding to GABAA receptors on the GABA-benzodiazepine receptor complex at the somatic level of hippocampal pyramidal neurons increases the chloride conductance of the membrane. This causes hyperpolarization and shunting of excitatory synaptic currents. 

Figure 11.6 Schematic representation of the GABAa receptor complex. Examples of the many structurally diverse compounds that act at different sites on the receptor (see text for details). Picrotoxinin, the active component of picrotoxin, and TBPS act as non-competitive antagonists. The barbiturates, steroids and anaesthetics are positive allosteric modulators, as are the benzodiazepine site ligands shown, with the exception of DMCM (negative allosteric modulator) and flumazenil (benzodiazepine site antagonist)...

Dysfunction of the GABAa receptor complex such that the effects of all benzodiazepine receptor ligands are shifted in the direction of inverse agonism. In this case, fiumazenil (which normally has zero efficacy) should induce anxiety in anxious patients but have no effects in healthy subjects because they have normal receptors. 

The GABA-gated chloride ion channel is modulated by several classes of drugs that bind to allosteric sites on the receptor complex the benzodiazepines, barbiturates and related intravenous general anesthetics such as etomidate and propofol, as well as anesthetic steroids and endogenous neurosteroids. It appears that some types of GABAa receptor are directly enhanced by ethanol and volatile general anesthetics (Fig. 16-2) [7,8,20]. 

Dekermendjian, K. et al., Structure-activity relationships and molecular modeling analysis of flavonoids binding to the benzodiazepine site of the rat brain GABAa receptor complex, J. Med. Chem., 42, 4343, 1999. 

Zaleplon has a pharmacological profile similar to benzodiazepines. Zaleplon is a full agonist for the benzodiazepine oq receptor located on the GABAa receptor ionophore complex in the brain, with lower affinity for the a2 and a3 subtypes. It selectively enhances the action of GABA similar to but more selectively than benzodiazepines. Zaleplon, although not benzodiazepine-like in chemical structure, induces sedative-hypnotic, anticonvulsant, and anticonflict effects via its binding to the central nervous system (CNS)-type benzodiazepine receptors [33-36]. 

Figure 11.7 Schematic three-dimensional representation of the GABAa receptor complex with the recognition sites for GABA, benzodiazepines, alcohol, steroids, and barbiturates.

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