Patch clamp reveals powerful blockade of the mitochondrial permeability transition pore by the D2-receptor agonist pramipexole.
The dopamine-D2-agonist pramipexole (PPX) was tested for blocking mitochondrial permeability transition (PT) in order to give a possible explanation for its neuroprotective effect seen in PPX-treated Parkinson's disease patients. Patch-clamp techniques for studying single-channel currents in the inner mitochondrial membrane and large-amplitude swelling of energized mitochondria were used to study PPX action on the permeability transition pore (PTP), a key player in the mitochondrial route of the apoptotic cascade. Identity of the PTP was proven by measuring the concentration-response relation for cyclosporin A-blockade (IC50=26 nM). PPX inhibits the PTP reversibly with an IC50 of 500 nM, which is close to the values determined earlier as plasma concentrations after PPX medication in patients. Interaction of PPX with the PTP is further supported by demonstrating that it abolished Ca2+-triggered swelling in functionally intact mitochondria. Blockade of the PTP by PPX was attenuated by increasing concentrations of inorganic phosphate and by acidification. We suggest that PPX could exert part of its neuroprotective effect by inhibition of the PTP and thus, probably, blocking of the mitochondrial pathway of the apoptosis cascade.
Sayeed
Iqbal
I
Department of Neurology, University of Magdeburg, Magdeburg, Germany.
Parvez
Suhel
S
Winkler-Stuck
Kirstin
K
Seitz
Gordon
G
Trieu
Isabelle
I
Wallesch
Claus-Werner
CW
Schönfeld
Peter
P
Siemen
Detlef
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D052160:Benzothiazoles; D002118:Calcium / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology; D007473:Ion Channels / Q000187:drug effects*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000235:genetics* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018384:Oxidative Stress; D018408:Patch-Clamp Techniques; D000077487:Pramipexole; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000494:pharmacology*
D052160:Benzothiazoles; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D013844:Thiazoles; D000077487:Pramipexole; D002118:Calcium; D004298:Dopamine