The Peripheral Benzodiazepine Receptor Modulates Ca2+Transport through the VDAC in Rat Heart Mitochondria

Journal of Clinical and Basic Cardiology 2008; 11 (1-4): 24-29

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Keywords: benzodiazepine receptor,  calcium,  Mitochondria,  MPT,  permeability transition,  translocator protein,  VDAC,  voltae dependent anion channel

The voltage-dependent anion channel (VDAC) is a key mitochondrial protein involved in the transport of calcium. Its function is, in part,regulated by associated proteins such as the 18 kD peripheral benzodiazepine receptor (PBR). We tested the hypothesis that an endogenous ligand of the PBR, hemin, could modulate calcium transport by modifying VDAC conductance. In isolated rat cardiac mitochondria, hemin (0–10 μM) exhibited multiple, time-dependent effects. Initially, hemin reduced the calcium uptake rate in a dose-dependent manner, an effect independent of the mitochondrial permeability transition (MPT) as it was not altered by cyclosporine A (CsA). However, subsequent to this inhibitory effect on calcium influx, hemin facilitated MPT as evidenced by greater calcium release following calcium loading. An inhibitory effect of hemin on VDAC conductance was supported by lipid bilayer experiments in which hemin induced channel closure of the VDAC-PBR-ANT complex. These findings indicate that the PBR ligand hemin has complex effects on mitochondrial calcium uptake, consistent with a PBR-dependent effect on VDAC conductance.