K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons.
The selective degeneration of dopaminergic (DA) midbrain neurons in the substantia nigra (SN) is a hallmark of Parkinson disease. DA neurons in the neighboring ventral tegmental area (VTA) are significantly less affected. The mechanisms for this differential vulnerability of DA neurons are unknown. We identified selective activation of ATP-sensitive potassium (K-ATP) channels as a potential mechanism. We show that in response to parkinsonism-inducing toxins, electrophysiological activity of SN DA neurons, but not VTA DA neurons, is lost owing to activation of K-ATP channels. This selective K-ATP channel activation is controlled by differences in mitochondrial uncoupling between SN and VTA DA neurons. Genetic inactivation of the K-ATP channel pore-forming subunit Kir6.2 resulted in a selective rescue of SN but not VTA DA neurons in two mechanistically distinct mouse models of dopaminergic degeneration, the neurotoxicological 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model and the mutant weaver mouse. Thus, K-ATP channel activation has an unexpected role in promoting death of DA neurons in chronic disease.
Liss
Birgit
B
Molecular Neurobiology, Department of Physiology, Marburg University Deutschhausstrasse 2, 35037 Marburg, Germany. birgit.liss@staff.uni-marburg.de
Haeckel
Olga
O
Wildmann
Johannes
J
Miki
Takashi
T
Seino
Susumu
S
Roeper
Jochen
J
D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D042967:Electron Transport Complex I / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000494:pharmacology; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000502:physiology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D020734:Parkinsonian Disorders; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism* / Q000503:physiopathology; D017557:Ventral Tegmental Area / Q000378:metabolism* / Q000503:physiopathology; D000099161:Kcnj11 Channel
D004298:Dopamine; D042967:Electron Transport Complex I; D009498:Neurotoxins; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel; C117780:mitochondrial K(ATP) channel