Nature Neuroscience 8, 1742 - 1751 (2005)
Published online: 20 November 2005; | doi:10.1038/nn1570
K-ATP channels promote the differential degeneration of dopaminergic midbrain neuronsBirgit Liss1, 2, 3, Olga Haeckel1, Johannes Wildmann4, Takashi Miki5, Susumu Seino5
& Jochen Roeper2, 61
Molecular Neurobiology, Department of Physiology, Marburg University Deutschhausstrasse 2, 35037 Marburg, Germany. 2
MRC Anatomical Neuropharmacology Unit, Oxford University, Mansfield Road, Oxford OX1 3TH, UK. 3
University Laboratory of Physiology, Oxford University, Parks Road, Oxford OX1 3PT, UK. 4
Immunology, Department of Physiology, Marburg University, Deutschhausstrasse 2, 35037 Marburg, Germany. 5
Cellular and Molecular Medicine, University Graduate School of Medicine, 7-5-1 Kusunoki-cho, 650-0017 Kobe, Japan. 6
Neurophysiology, Department of Physiology, Marburg University, Deutschhausstrasse 2, 35037 Marburg, Germany.
Correspondence should be addressed to Birgit Liss birgit.liss@staff.uni-marburg.de 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.
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