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Patch clamp reveals powerful blockade of the mitochondrial permeability transition pore by the D2‐receptor agonist pramipexole
Author(s) -
Sayeed Iqbal,
Parvez Suhel,
WinklerStuck Kirstin,
Seitz Gordon,
Trieu Isabelle,
Wallesch ClausWerner,
Schönfeld Peter,
Siemen Detlef
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-4748fje
Subject(s) - mitochondrial permeability transition pore , pramipexole , chemistry , agonist , mitochondrion , neuroprotection , inner mitochondrial membrane , membrane potential , biophysics , pharmacology , receptor , apoptosis , biochemistry , programmed cell death , biology , medicine , parkinson's disease , disease
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 Ca 2+ ‐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.