MOLECULAR-BASIS FOR THE DIFFERENT BINDING-PROPERTIES OF BENZODIAZEPINES TO HUMAN AND BOVINE PERIPHERAL-TYPE BENZODIAZEPINE RECEPTORS

The 18 kDa peripheral benzodiazepine receptor (PBR) can be labelled by benzodiazepines, such as Ro5-864, and isoquinoline carboxamides such as PK11195. These two compounds are reversible competitive inhibitors of each other. However, while the binding affinity of Ro5-4864 varies enormously across species, PK11195 always displays high-affinity, suggesting that their binding domains are overlapping but not identical. We report here that recombinant human and bovine PBR produced in yeast, a microorganism devoid of endogenous PBR, can be labelled with [H-3]PK11195, but only the human receptor can be labelled with [H-3]Ro5-1864. Furthermore, we identified, through the binding analysis of human-bovine chimaeric receptors, a region near the C-terminal end of the PBR, with only five non-conserved amino acids between human and bovine sequences, as responsible for the difference in high affinity binding of Ro5-4864 to the two receptors.