In search of the function of the peripheral-type benzodiazepine receptor

Abstract

The peripheral-type benzodiazepine receptor (PBR) is a mitochondrial protein, involved in the regulation of cholesterol transport from the outer to the inner mitochondrial membrane, the rate-determining step in steroid hormone biosynthesis. Molecular modeling of PBR suggested that it might function as a channel for cholesterol. Indeed, cholesterol uptake and transport by bacteria cells was induced upon PBR expression. Amino acid deletion, site-directed mutagenesis, and structural studies identified a cholesterol recognition/interaction amino acid consensus sequence in the cytoplasmic carboxy-terminus of the receptor. In vitro reconstitution experiments demonstrated that the 18 kDa PBR protein binds with high affinity both drug ligands and cholesterol. In situ and in vitro studies indicated that in steroidogenic cells the StAR-induced cholesterol import into mitochondria was mediated by the outer mitochondrial membrane PBR. In search of the tissue specificity of PBR expression it was shown that the high levels of PBR expression in steroidogenic cells are due, at least in part, to the expression of Sp1/Sp3 transcription factors. Moreover, PBR's function in cholesterol transport was found to be conserved across kingdoms because a PBR-homologous Arabidopsis sequence when expressed in bacteria protoplasts caused a ligand-induced uptake of cholesterol suggesting that the Arabidopsis PBR homologue is involved in steroid import in plant mitochondria. In conclusion, these studies suggest that PBR's ability to bind and transport cholesterol is a well-conserved function of this ubiquitous protein. Expression of specific transcription factors results in the overexpression of PBR and increased cholesterol transport into mitochondria associated with a specialized function (steroidogenesis). In other tissues, PBR expression might be part of the mitochondrial membrane biogenesis process involved in increased cell proliferation (cancer, gliosis) and tissue repair (nerve damage and ischemia-reperfusion injury).