title: Inhibition of the mitochondrial F1F0-ATPase by ligands of the peripheral benzodiazepine receptor.
abstract: Although PK11195 binds to the peripheral benzodiazepine receptor with nanomolar affinity, significant data exist which suggest that it has another cellular target distinct from the PBR. Here we demonstrate that PK11195 inhibits F(1)F(0)-ATPase activity in an OSCP-dependent manner, similar to the pro-apoptotic benzodiazepine Bz-423. Importantly, our data indicate that cellular responses observed with micromolar concentrations of PK11195, which are commonly attributed to modulation of the PBR, are likely a direct result of mitochondrial F(1)F(0)-ATPase inhibition.
authors.affiliation: Department of Chemistry, University of Michigan, 930 N University Ave., Ann Arbor, MI 48109-1055, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Cleary
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Johnson
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Opipari
authors.forename: Gary D
authors.initials: GD
authors.lastname: Glick
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058787:GABA-A Receptor Antagonists; D006801:Humans; D006868:Hydrolysis; D007546:Isoquinolines / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008928:Mitochondria / Q000201:enzymology*; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D058787:GABA-A Receptor Antagonists; D007546:Isoquinolines; D008024:Ligands; D001569:Benzodiazepines; D000255:Adenosine Triphosphate; D006180:Proton-Translocating ATPases; C037850:PK 11195