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Volume 272, Number 44, Issue of October 31, 1997 pp. 28102-28106
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

The M_r 18,000 Subunit of the Peripheral-type Benzodiazepine Receptor Exhibits Both Benzodiazepine and Isoquinoline Carboxamide Binding Sites in the Absence of the Voltage-dependent Anion Channel or of the Adenine Nucleotide Carrier

(Received for publication, June 9, 1997, and in revised form, August 7, 1997)

Evelyne Joseph-Liauzun , Roseli Farges ^¶ , Pascal Delmas ^¶ , Pascual Ferrara ^¶ and Gérard Loison

From the Departments of  Microbiology and ^¶ Protein Biochemistry, Sanofi-Recherche, BP 137, F-31676 Labège Cédex, France

The peripheral type benzodiazepine receptor (PBR) binds benzodiazepines such as RO5-4864 and isoquinoline carboxamide derivatives such as PK11195. This receptor includes an M_r 18,000 isoquinoline-binding subunit predominantly located in mitochondrial mem- branes. This protein has been found to copurify with two other mitochondrial proteins, namely the outer membrane voltage-dependent anion channel (VDAC), also known as mitochondrial porin, and the inner membrane adenine nucleotide carrier. In vitro reconstitution experiments suggested that the PBR was a multimeric complex in which the isoquinoline binding site was on the M_r 18,000 subunit, denoted pk18, whereas the benzodiazepine binding site required the association of this subunit with VDAC to be expressed. Untransformed cells of the yeast Saccharomyces cerevisiae are devoid of specific binding sites for isoquinolines and benzodiazepines, whereas yeast cells transformed with a pk18-expressing vector exhibit RO5-4864 and PK11195 binding sites that are pharmacologically identical to those of the PBR. To clarify the role of VDAC and of the adenine nucleotide carrier, if any, in the constitution of the benzodiazepine binding site, yeast host strains were constructed in which the corresponding genes had been knocked out. Mitochondria prepared from pk18-producing cells devoid of either VDAC or adenine nucleotide carrier exhibit both benzodiazepine and isoquinoline carboxamide binding sites with little or no change in the K_d values as compared with the wild-type background. These results rule out the contention that VDAC is indispensable for establishing the benzodiazepine binding site and are in agreement with the hypothesis that the M_r 18,000 subunit carries both the isoquinoline carboxamide and benzodiazepine binding domains.

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