Abstract
"Peripheral-type" benzodiazepine receptors are localized to the outer mitochondrial membrane. We have identified potent competitive inhibitors of these receptors and purified them from human blood and from several rat organs. TLC analysis of the purified inhibitor from erythrocytes displays a single peak of inhibitory activity with an absorbance spectrum identical to hemin. All of the inhibitory activity in extracts of several tissues can be accounted for by their porphyrin and metalloporphyrin content. Pure hemin and protoporphyrin IX competitively inhibit mitochondrial benzodiazepine binding with Ki values of 41 and 15 nM, respectively, and are less active by a factor of 1000 at central-type benzodiazepine receptors. Thus, porphyrins appear to be endogenous ligands for mitochondrial benzodiazepine receptors.
Full text
PDF![2256](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6496/304628/adba18e07c07/pnas00273-0154.png)
![2257](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6496/304628/212be1925e86/pnas00273-0155.png)
![2258](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6496/304628/29b0eb9ab94b/pnas00273-0156.png)
![2259](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6496/304628/9e07d5931d34/pnas00273-0157.png)
![2260](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6496/304628/4db1c94b63c0/pnas00273-0158.png)
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Anholt R. R., Aebi U., Pedersen P. L., Snyder S. H. Solubilization and reassembly of the mitochondrial benzodiazepine receptor. Biochemistry. 1986 Apr 22;25(8):2120–2125. doi: 10.1021/bi00356a041. [DOI] [PubMed] [Google Scholar]
- Anholt R. R., Pedersen P. L., De Souza E. B., Snyder S. H. The peripheral-type benzodiazepine receptor. Localization to the mitochondrial outer membrane. J Biol Chem. 1986 Jan 15;261(2):576–583. [PubMed] [Google Scholar]
- Beaumont K., Cheung A. K., Geller M. L., Fanestil D. D. Inhibitors of peripheral-type benzodiazepine receptors present in human urine and plasma ultrafiltrates. Life Sci. 1983 Oct 3;33(14):1375–1384. doi: 10.1016/0024-3205(83)90820-2. [DOI] [PubMed] [Google Scholar]
- Bénavidès J., Guilloux F., Allam D. E., Uzan A., Mizoule J., Renault C., Dubroeucq M. C., Guérémy C., Le Fur G. Opposite effects of an agonist, RO5-4864, and an antagonist, PK 11195, of the peripheral type benzodiazepine binding sites on audiogenic seizures in DBA/2J mice. Life Sci. 1984 Jun 25;34(26):2613–2620. doi: 10.1016/0024-3205(84)90048-1. [DOI] [PubMed] [Google Scholar]
- Clarke G. D., Ryan P. J. Tranquillizers can block mitogenesis in 3T3 cells and induce differentiation in Friend cells. Nature. 1980 Sep 11;287(5778):160–161. doi: 10.1038/287160a0. [DOI] [PubMed] [Google Scholar]
- Clow A., Glover V., Armando I., Sandler M. New endogenous benzodiazepine receptor ligand in human urine: identity with endogenous monoamine oxidase inhibitor? Life Sci. 1983 Aug 22;33(8):735–741. doi: 10.1016/0024-3205(83)90778-6. [DOI] [PubMed] [Google Scholar]
- Curran T., Morgan J. I. Superinduction of c-fos by nerve growth factor in the presence of peripherally active benzodiazepines. Science. 1985 Sep 20;229(4719):1265–1268. doi: 10.1126/science.4035354. [DOI] [PubMed] [Google Scholar]
- De Pinto V., Tommasino M., Benz R., Palmieri F. The 35 kDa DCCD-binding protein from pig heart mitochondria is the mitochondrial porin. Biochim Biophys Acta. 1985 Mar 14;813(2):230–242. doi: 10.1016/0005-2736(85)90238-x. [DOI] [PubMed] [Google Scholar]
- Elsworth J. D., Dewar D., Glover V., Goodwin B. L., Clow A., Sandler M. Purification and characterization of tribulin, and endogenous inhibitor of monoamine oxidase and of benzodiazepine receptor binding. J Neural Transm. 1986;67(1-2):45–56. doi: 10.1007/BF01243358. [DOI] [PubMed] [Google Scholar]
- Guidotti A., Forchetti C. M., Corda M. G., Konkel D., Bennett C. D., Costa E. Isolation, characterization, and purification to homogeneity of an endogenous polypeptide with agonistic action on benzodiazepine receptors. Proc Natl Acad Sci U S A. 1983 Jun;80(11):3531–3535. doi: 10.1073/pnas.80.11.3531. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Guidotti A., Santi M. R., Berkovich A., Ferrarese C., Costa E. Structure-activity relationship of peptide fragments derived from DBI (diazepam binding inhibitor), a putative endogenous ligand of benzodiazepine recognition sites. Clin Neuropharmacol. 1986;9 (Suppl 4):217–219. [PubMed] [Google Scholar]
- Hunkeler W., Möhler H., Pieri L., Polc P., Bonetti E. P., Cumin R., Schaffner R., Haefely W. Selective antagonists of benzodiazepines. Nature. 1981 Apr 9;290(5806):514–516. doi: 10.1038/290514a0. [DOI] [PubMed] [Google Scholar]
- JENSEN J. Separation of the coproporphyrin isomers I and III by thin layer chromatography. J Chromatogr. 1963 Feb;10:236–238. doi: 10.1016/s0021-9673(01)92298-8. [DOI] [PubMed] [Google Scholar]
- Kennedy S. W., Wigfield D. C., Fox G. A. Tissue porphyrin pattern determination by high-speed high-performance liquid chromatography. Anal Biochem. 1986 Aug 15;157(1):1–7. doi: 10.1016/0003-2697(86)90187-9. [DOI] [PubMed] [Google Scholar]
- Mantione C. R., Weissman B. A., Goldman M. E., Paul S. M., Skolnick P. Endogenous inhibitors of 4'-[3H]chlorodiazepam (Ro 5-4864) binding to 'peripheral' sites for benzodiazepines. FEBS Lett. 1984 Oct 15;176(1):69–74. doi: 10.1016/0014-5793(84)80913-8. [DOI] [PubMed] [Google Scholar]
- Mestre M., Bouetard G., Uzan A., Gueremy C., Renault C., Dubroeucq M. C., Le Fur G. PK 11195, an antagonist of peripheral benzodiazepine receptors, reduces ventricular arrhythmias during myocardial ischemia and reperfusion in the dog. Eur J Pharmacol. 1985 Jun 7;112(2):257–260. doi: 10.1016/0014-2999(85)90505-9. [DOI] [PubMed] [Google Scholar]
- Mestre M., Carriot T., Belin C., Uzan A., Renault C., Dubroeucq M. C., Guérémy C., Doble A., Le Fur G. Electrophysiological and pharmacological evidence that peripheral type benzodiazepine receptors are coupled to calcium channels in the heart. Life Sci. 1985 Jan 28;36(4):391–400. doi: 10.1016/0024-3205(85)90126-2. [DOI] [PubMed] [Google Scholar]
- Mestre M., Carriot T., Néliat G., Uzan A., Renault C., Dubroeucq M. C., Guérémy C., Doble A., Le Fur G. PK 11195, an antagonist of peripheral type benzodiazepine receptors, modulates Bay K8644 sensitive but not beta- or H2-receptor sensitive voltage operated calcium channels in the guinea pig heart. Life Sci. 1986 Jul 28;39(4):329–339. doi: 10.1016/0024-3205(86)90651-x. [DOI] [PubMed] [Google Scholar]
- Parry D. M., Pedersen P. L. Intracellular localization of rat kidney hexokinase. Evidence for an association with low density mitochondria. J Biol Chem. 1984 Jul 25;259(14):8917–8923. [PubMed] [Google Scholar]
- Ruff M. R., Pert C. B., Weber R. J., Wahl L. M., Wahl S. M., Paul S. M. Benzodiazepine receptor-mediated chemotaxis of human monocytes. Science. 1985 Sep 20;229(4719):1281–1283. doi: 10.1126/science.2994216. [DOI] [PubMed] [Google Scholar]
- Schoemaker H., Boles R. G., Horst W. D., Yamamura H. I. Specific high-affinity binding sites for [3H]Ro 5-4864 in rat brain and kidney. J Pharmacol Exp Ther. 1983 Apr;225(1):61–69. [PubMed] [Google Scholar]
- Shoyab M., Gentry L. E., Marquardt H., Todaro G. J. Isolation and characterization of a putative endogenous benzodiazepineoid (endozepine) from bovine and human brain. J Biol Chem. 1986 Sep 15;261(26):11968–11973. [PubMed] [Google Scholar]
- Wang J. K., Morgan J. I., Spector S. Benzodiazepines that bind at peripheral sites inhibit cell proliferation. Proc Natl Acad Sci U S A. 1984 Feb;81(3):753–756. doi: 10.1073/pnas.81.3.753. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wang J. K., Morgan J. I., Spector S. Differentiation of Friend erythroleukemia cells induced by benzodiazepines. Proc Natl Acad Sci U S A. 1984 Jun;81(12):3770–3772. doi: 10.1073/pnas.81.12.3770. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weiss S. R., Post R. M., Patel J., Marangos P. J. Differential mediation of the anticonvulsant effects of carbamazepine and diazepam. Life Sci. 1985 Jun 24;36(25):2413–2419. doi: 10.1016/0024-3205(85)90345-5. [DOI] [PubMed] [Google Scholar]
- Weissman B. A., Bolger G. T., Isaac L., Paul S. M., Skolnick P. Characterization of the binding of [3H]Ro 5-4864, a convulsant benzodiazepine, to guinea pig brain. J Neurochem. 1984 Apr;42(4):969–975. doi: 10.1111/j.1471-4159.1984.tb12698.x. [DOI] [PubMed] [Google Scholar]
- Weissman B. A., Cott J., Jackson J. A., Bolger G. T., Weber K. H., Horst W. D., Paul S. M., Skolnick P. "Peripheral-type" binding sites for benzodiazepines in brain: relationship to the convulsant actions of Ro 5-4864. J Neurochem. 1985 May;44(5):1494–1499. doi: 10.1111/j.1471-4159.1985.tb08787.x. [DOI] [PubMed] [Google Scholar]
- Wildmann J., Niemann J., Matthaei H. Endogenous benzodiazepine receptor agonist in human and mammalian plasma. J Neural Transm. 1986;66(3-4):151–160. doi: 10.1007/BF01260910. [DOI] [PubMed] [Google Scholar]