Combined effect of G3139 and TSPO ligands on Ca(2+)-induced permeability transition in rat brain mitochondria.
Permeability of the mitochondrial outer membrane is determined by the activity of voltage-dependent anion channels (VDAC) which are regulated by many factors and proteins. One of the main partner-regulator of VDAC is the 18 kDa translocator protein (TSPO), whose role in the regulation of membrane permeability is not completely understood. We show that TSPO ligands, 1 μM PPIX and PK11195 at concentrations of 50 μM, accelerate opening of permeability transition pores (mPTP) in Ca(2+)-overloaded rat brain mitochondria (RBM). By contrast, PK11195 at 100 nM and anti-TSPO antibodies suppressed pore opening. Participation of VDAC in these processes was demonstrated by blocking VDAC with G3139, an 18-mer phosphorothioate oligonucleotides, which sensitized mitochondria to Ca(2+)-induced mPTP opening. Despite the inhibitory effect of 100 nM PK11195 and anti-TSPO antibodies alone, their combination with G3139 considerably stimulated the mPTP opening. Thus, 100 nM PK11195 and anti-TSPO antibody can modify permeability of the VDAC channel and mPTP. When VDAC channels are closed and TSPO is blocked, permeability of the VDAC for calcium seems to be the highest, which leads to accelerated pore opening.
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya Str., Pushchino, Moscow Region, 142290, Russia. Electronic address: tamara.azarashvili@gmail.com.
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Azarashvili
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya Str., Pushchino, Moscow Region, 142290, Russia. Electronic address: krestinina@rambler.ru.
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Krestinina
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya Str., Pushchino, Moscow Region, 142290, Russia. Electronic address: byul@rambler.ru.
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Baburina
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya Str., Pushchino, Moscow Region, 142290, Russia. Electronic address: odinokova@rambler.ru.
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Odinokova
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya Str., Pushchino, Moscow Region, 142290, Russia. Electronic address: grachew@rambler.ru.
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Grachev
The Research Institute of the McGill University Health Center, and Departments of Medicine, Biochemistry, Pharmacology and Therapeutics, McGill University, 2155 Guy Street, Montreal, Que., H3H 2R9, Canada. Electronic address: vassilios.papadopoulos@mcgill.ca.
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Papadopoulos
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya Str., Pushchino, Moscow Region, 142290, Russia. Electronic address: akatov.vladimir@gmail.com.
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Akatov
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya Str., Pushchino, Moscow Region, 142290, Russia; Departments of Drug Discovery & Biomedical Sciences and Biochemistry & Molecular Biology, Medical University of South Carolina, DD504 Drug Discovery Bldg., 70 President St., MSC 140, Charleston, SC, 29425, USA. Electronic address: JJLemasters@musc.edu.
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Lemasters
Institut für Neurobiochemie, Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Leipziger Str. 44, 39120, Magdeburg, Germany. Electronic address: georg.reiser@med.ovgu.de.
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Reiser
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002413:Cations, Divalent / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology*; D008024:Ligands; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D010539:Permeability / Q000187:drug effects; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D013873:Thionucleotides / Q000494:pharmacology*; D050994:Voltage-Dependent Anion Channels / Q000037:antagonists & inhibitors*
D002352:Carrier Proteins; D002413:Cations, Divalent; D007546:Isoquinolines; D008024:Ligands; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011963:Receptors, GABA-A; D013873:Thionucleotides; D050994:Voltage-Dependent Anion Channels; C069997:Tspo protein, rat; C408162:oblimersen; D002118:Calcium; C037850:PK 11195
G3139; Mitochondria; PK11195; Permeability transition pore; TSPO; VDAC