Skip to main content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Proc Natl Acad Sci U S A. 1993 Feb 15; 90(4): 1374–1378.
doi: 10.1073/pnas.90.4.1374
PMCID: PMC45875
PMID: 7679505

Mitochondrial benzodiazepine receptor linked to inner membrane ion channels by nanomolar actions of ligands.

K W Kinnally, D B Zorov, Y N Antonenko, S H Snyder, M W McEnery, and H Tedeschi
Author information Copyright and License information PMC Disclaimer

Abstract

The mitochrondrial benzodiazepine receptor (mBzR) binds a subset of benzodiazepines and isoquinoline carboxamides with nanomolar affinity and consists of the voltage-dependent anion channel, the adenine nucleotide translocator, and an 18-kDa protein. The effect of ligands of the mBzR on two inner mitochondrial membrane channel activities was determined with patch-clamp techniques. The relative inhibitory potencies of the drugs resemble their binding affinities for the mBzR. Ro5-4864 and protoporphyrin IX inhibit activity of the multiple conductance channel (MCC) and the mitochondrial centum-picosiemen (mCtS) channel activities at nanomolar concentrations. PK11195 inhibits mCtS activity at similar levels. Higher concentrations of protoporphyrin IX induce MCC but possibly not mCtS activity. Clonazepam, which has low affinity for mBzR, is at least 500 times less potent at both channel activities. Ro15-1788, which also has a low mBzR affinity, inhibits MCC at very high concentrations (16 microM). The findings indicate an association of these two channel activities with the proteins forming the mBzR complex and are consistent with an interaction of inner and outer membrane channels.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (975K), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

 
icon of scanned page 1374
1374
icon of scanned page 1375
1375
icon of scanned page 1376
1376
icon of scanned page 1377
1377
icon of scanned page 1378
1378
 

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  • Tallman JF, Paul SM, Skolnick P, Gallager DW. Receptors for the age of anxiety: pharmacology of the benzodiazepines. Science. 1980 Jan 18;207(4428):274–281. [PubMed] [Google Scholar]
  • Moreno-Sánchez R, Hogue BA, Bravo C, Newman AH, Basile AS, Chiang PK. Inhibition of substrate oxidation in mitochondria by the peripheral-type benzodiazepine receptor ligand AHN 086. Biochem Pharmacol. 1991 May 15;41(10):1479–1484. [PubMed] [Google Scholar]
  • Vorobjev IA, Zorov DB. Diazepam inhibits cell respiration and induces fragmentation of mitochondrial reticulum. FEBS Lett. 1983 Nov 14;163(2):311–314. [PubMed] [Google Scholar]
  • Hirsch JD, Beyer CF, Malkowitz L, Beer B, Blume AJ. Mitochondrial benzodiazepine receptors mediate inhibition of mitochondrial respiratory control. Mol Pharmacol. 1989 Jan;35(1):157–163. [PubMed] [Google Scholar]
  • Basile AS, Bolger GT, Lueddens HW, Skolnick P. Electrophysiological actions of Ro5-4864 on cerebellar Purkinje neurons: evidence for "peripheral" benzodiazepine receptor-mediated depression. J Pharmacol Exp Ther. 1989 Jan;248(1):463–469. [PubMed] [Google Scholar]
  • Mestre M, Carriot T, Belin C, Uzan A, Renault C, Dubroeucq MC, Guérémy C, Le Fur G. Electrophysiological and pharmacological characterization of peripheral benzodiazepine receptors in a guinea pig heart preparation. Life Sci. 1984 Aug 27;35(9):953–962. [PubMed] [Google Scholar]
  • Papadopoulos V, Mukhin AG, Costa E, Krueger KE. The peripheral-type benzodiazepine receptor is functionally linked to Leydig cell steroidogenesis. J Biol Chem. 1990 Mar 5;265(7):3772–3779. [PubMed] [Google Scholar]
  • Krueger KE, Papadopoulos V. Peripheral-type benzodiazepine receptors mediate translocation of cholesterol from outer to inner mitochondrial membranes in adrenocortical cells. J Biol Chem. 1990 Sep 5;265(25):15015–15022. [PubMed] [Google Scholar]
  • Krueger KE, Papadopoulos V. Mitochondrial benzodiazepine receptors and the regulation of steroid biosynthesis. Annu Rev Pharmacol Toxicol. 1992;32:211–237. [PubMed] [Google Scholar]
  • McEnery MW, Snowman AM, Trifiletti RR, Snyder SH. Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3170–3174. [PMC free article] [PubMed] [Google Scholar]
  • Hackenbrock CR. Chemical and physical fixation of isolated mitochondria in low-energy and high-energy states. Proc Natl Acad Sci U S A. 1968 Oct;61(2):598–605. [PMC free article] [PubMed] [Google Scholar]
  • Moran O, Sandri G, Panfili E, Stühmer W, Sorgato MC. Electrophysiological characterization of contact sites in brain mitochondria. J Biol Chem. 1990 Jan 15;265(2):908–913. [PubMed] [Google Scholar]
  • Kinnally KW, Antonenko YN, Zorov DB. Modulation of inner mitochondrial membrane channel activity. J Bioenerg Biomembr. 1992 Feb;24(1):99–110. [PubMed] [Google Scholar]
  • Sorgato MC, Keller BU, Stühmer W. Patch-clamping of the inner mitochondrial membrane reveals a voltage-dependent ion channel. Nature. 1987 Dec 3;330(6147):498–500. [PubMed] [Google Scholar]
  • Hirsch JD, Beyer CF, Malkowitz L, Loullis CC, Blume AJ. Characterization of ligand binding to mitochondrial benzodiazepine receptors. Mol Pharmacol. 1989 Jan;35(1):164–172. [PubMed] [Google Scholar]
  • Verma A, Snyder SH. Characterization of porphyrin interactions with peripheral type benzodiazepine receptors. Mol Pharmacol. 1988 Dec;34(6):800–805. [PubMed] [Google Scholar]
  • Campo ML, Kinnally KW, Tedeschi H. The effect of antimycin A on mouse liver inner mitochondrial membrane channel activity. J Biol Chem. 1992 Apr 25;267(12):8123–8127. [PubMed] [Google Scholar]
  • Decker GL, Greenawalt JW. Ultrastructural and biochemical studies of mitoplasts and outer membranes derived from French-pressed mitochondria. Advances in mitochondrial subfractionation. J Ultrastruct Res. 1977 Apr;59(1):44–56. [PubMed] [Google Scholar]
  • Zorov DB, Kinnally KW, Perini S, Tedeschi H. Multiple conductance levels in rat heart inner mitochondrial membranes studied by patch clamping. Biochim Biophys Acta. 1992 Apr 13;1105(2):263–270. [PubMed] [Google Scholar]
  • Costa G, Kinnally KW, Diwan JJ. Patch clamp analysis of a partially purified ion channel from rat liver mitochondria. Biochem Biophys Res Commun. 1991 Feb 28;175(1):305–310. [PubMed] [Google Scholar]
  • Ruknudin A, Song MJ, Sachs F. The ultrastructure of patch-clamped membranes: a study using high voltage electron microscopy. J Cell Biol. 1991 Jan;112(1):125–134. [PMC free article] [PubMed] [Google Scholar]
  • Szabó I, Zoratti M. The giant channel of the inner mitochondrial membrane is inhibited by cyclosporin A. J Biol Chem. 1991 Feb 25;266(6):3376–3379. [PubMed] [Google Scholar]
  • Antonenko YN, Kinnally KW, Perini S, Tedeschi H. Selective effect of inhibitors on inner mitochondrial membrane channels. FEBS Lett. 1991 Jul 8;285(1):89–93. [PubMed] [Google Scholar]
  • Moczydlowski E, Latorre R. Gating kinetics of Ca2+-activated K+ channels from rat muscle incorporated into planar lipid bilayers. Evidence for two voltage-dependent Ca2+ binding reactions. J Gen Physiol. 1983 Oct;82(4):511–542. [PMC free article] [PubMed] [Google Scholar]
  • Beavis AD. Properties of the inner membrane anion channel in intact mitochondria. J Bioenerg Biomembr. 1992 Feb;24(1):77–90. [PubMed] [Google Scholar]
  • Sandri G, Siagri M, Panfili E. Influence of Ca2+ on the isolation from rat brain mitochondria of a fraction enriched of boundary membrane contact sites. Cell Calcium. 1988 Aug;9(4):159–165. [PubMed] [Google Scholar]
  • Benz R, Brdiczka D. The cation-selective substate of the mitochondrial outer membrane pore: single-channel conductance and influence on intermembrane and peripheral kinases. J Bioenerg Biomembr. 1992 Feb;24(1):33–39. [PubMed] [Google Scholar]
  • Krause J, Hay R, Kowollik C, Brdiczka D. Cross-linking analysis of yeast mitochondrial outer membrane. Biochim Biophys Acta. 1986 Sep 11;860(3):690–698. [PubMed] [Google Scholar]
  • Nakashima RA, Mangan PS, Colombini M, Pedersen PL. Hexokinase receptor complex in hepatoma mitochondria: evidence from N,N'-dicyclohexylcarbodiimide-labeling studies for the involvement of the pore-forming protein VDAC. Biochemistry. 1986 Mar 11;25(5):1015–1021. [PubMed] [Google Scholar]
  • Weiler U, Riesinger I, Knoll G, Brdiczka D. The regulation of mitochondrial-bound hexokinases in the liver. Biochem Med. 1985 Apr;33(2):223–235. [PubMed] [Google Scholar]
  • Arora KK, Pedersen PL. Functional significance of mitochondrial bound hexokinase in tumor cell metabolism. Evidence for preferential phosphorylation of glucose by intramitochondrially generated ATP. J Biol Chem. 1988 Nov 25;263(33):17422–17428. [PubMed] [Google Scholar]
  • BeltrandelRio H, Wilson JE. Hexokinase of rat brain mitochondria: relative importance of adenylate kinase and oxidative phosphorylation as sources of substrate ATP, and interaction with intramitochondrial compartments of ATP and ADP. Arch Biochem Biophys. 1991 Apr;286(1):183–194. [PubMed] [Google Scholar]
  • McEnery MW. The mitochondrial benzodiazepine receptor: evidence for association with the voltage-dependent anion channel (VDAC). J Bioenerg Biomembr. 1992 Feb;24(1):63–69. [PubMed] [Google Scholar]
  • Snyder SH, Verma A, Trifiletti RR. The peripheral-type benzodiazepine receptor: a protein of mitochondrial outer membranes utilizing porphyrins as endogenous ligands. FASEB J. 1987 Oct;1(4):282–288. [PubMed] [Google Scholar]
  • Sprengel R, Werner P, Seeburg PH, Mukhin AG, Santi MR, Grayson DR, Guidotti A, Krueger KE. Molecular cloning and expression of cDNA encoding a peripheral-type benzodiazepine receptor. J Biol Chem. 1989 Dec 5;264(34):20415–20421. [PubMed] [Google Scholar]
  • Holden MJ, Colombini M. The mitochondrial outer membrane channel, VDAC, is modulated by a soluble protein. FEBS Lett. 1988 Dec 5;241(1-2):105–109. [PubMed] [Google Scholar]
  • Curran T, Morgan JI. Superinduction of c-fos by nerve growth factor in the presence of peripherally active benzodiazepines. Science. 1985 Sep 20;229(4719):1265–1268. [PubMed] [Google Scholar]
  • Okabe T, Fujisawa M, Takaku F. Long-term cultivation and differentiation of human erythroleukemia cells in a protein-free chemically defined medium. Proc Natl Acad Sci U S A. 1984 Jan;81(2):453–455. [PMC free article] [PubMed] [Google Scholar]
Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences
-