Among the allosteric receptor sites the sites for the benzodiazepines (Bz) are of prime importance since these ligands have been employed widely as anxiolytic/anticonvulsant agents since the 1960s. Studies of molecular biology have suggested that the GABAA/BzR complex is a heteropentameric protein polymer constituted principally from α, β and γ subunits. At present, a total of 16 subunits (6α, 4β, 3γ, 1δ, and 2ρ) have been isolated and identified from the CNS (15 of these have been found in the mammaliam CNS). Recent studies of recombinant GABAA/BzR have shown that the presence of α, β and γ subunits is necessary to constitute a fully functional benzodiazepine receptor/GABA/chloride ion channel which mimics the pharmacological, biochemical, and electrophysiological properties of a native receptor. From recombinant studies it appears that receptors constructed from αx, β2, and γ2 subunits most closely resemble the pharmacological profile of a native BzR substypes obtained from mammalian tissues:
• Receptor subtypes comprised of an α1 with β2γ2 subunits resembling the activity of the classical Bz-1 receptor subtype and found in the cerebellum (and elsewhere).
• Receptor substypes comprised of α2-, α3- or α5β2γ2 subunits mimic the activity of the Bz-2 recptor that is found principally in the cortex, hippocampus, and spinal cord.
• The Bz-3 receptors, constitute the "peripheral" receptors since they have been identified in the brain as well as in a wide range of peripheral tissues; their subcellular location has been reported to be mainly mitochondrial, and hence, this receptor is also termed "mitochondrial benzodiazepine receptor". Although the structure and parmacological role of the BZ3 receptors remains to be fully clarified, some evidence indicates their involvement in important cellular functions such as the production of neurosteroids.
