Parvez 2010 Biochim Biophys Acta
Parvez S, Winkler-Stuck K, Hertel S, Schoenfeld P, Siemen D (2010) The dopamine-D2-receptor agonist ropinirole dose-dependently blocks the Ca(2+)-triggered permeability transition of mitochondria. Biochim Biophys Acta 1797:1245-50. |
Parvez S, Winkler-Stuck K, Hertel S, Schoenfeld P, Siemen D (2010) Biochim Biophys Acta
Abstract: Ropinirole, an agonist of the post-synaptic dopamine D2-receptor, exerts neuroprotective activity. The mechanism is still under discussion. Assuming that this neuroprotection might be associated with inhibition of the apoptotic cascade underlying cell death, we examined a possible effect of ropinirole on the permeability transition pore (mtPTP) in the mitochondrial inner membrane. Using isolated rat liver mitochondria, the effect of ropinirole was studied on Ca2+-triggered large amplitude swelling, membrane depolarization and cytochrome c release. In addition, the effect of ropinirole on oxidation of added, membrane-impermeable NADH was investigated. The results revealed doubtlessly, that ropinirole can inhibit permeability transition. In patch-clamp experiments on mitoplasts, we show directly that ropinirole interacts with the mtPTP. Thus, ropinirole reversibly inhibits the opening of mtPTP with an IC(50) of 3.4microM and a Hill coefficient of 1.3. In both systems (i.e. energized mitochondria and mitoplasts) the inhibitory effect on permeability transition was attenuated by increasing concentrations of inorganic phosphate. In addition, we showed with antimycin A-treated mitochondria that ropinirole failed to suppress respiratory chain-linked reactive oxygen species release. In conclusion, our data suggest that the neuroprotective activity of ropinirole is due to the blockade of the Ca2+-triggered permeability transition. β’ Keywords: Parkinson's disease, Permeability transition, Apoptosis, Mitochondria, Ropinirole, Neuroprotection
β’ O2k-Network Lab: DE Magdeburg Siemen D, DE Magdeburg Schoenfeld P
Labels: MiParea: Respiration, Pharmacology;toxicology
Pathology: Parkinson's
Stress:Permeability transition
Organism: Rat
Tissue;cell: Liver
Preparation: Isolated mitochondria, Enzyme
Enzyme: Inner mt-membrane transporter
Regulation: Calcium, Inhibitor
Coupling state: OXPHOS
HRR: Oxygraph-2k
Abbreviations: CsA, cyclosporin A; Cyt c, cytochrome c; FCCP, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; IC50, inhibitor concentration causing 50% inhibition; mtPTP, mitochondrial permeability transition pore; PD, Parkinson's disease; RBM, rat brain mitochondria; RLM, rat liver mitochondria; ROS, reactive oxygen species; Pi, inorganic phosphate; Po, open probability; ΞΟm, mitochondrial membrane potential
Correction
An Oroboros O2k was used in this publication, whereas the Anton Paar/Oroboros Oxygraph was the first-generation instrument for high-resolution respirometry, which was replaced by the Oxygraph-2k in 2002.
- Further details: Gnaiger 2012 Abstract Bioblast-Gentle Science