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K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons

Nature Neuroscience volume 8, pages 1742–1751 (2005)Cite this article

Abstract

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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Figure 1: Properties of adult mesostriatal and mesolimbic DA neurons.
Figure 2: Kir6.2 forms the K-ATP channel pore in all DA neurons.
Figure 3: K-ATP subunit expression of individual laser-microdissected DA neurons.
Figure 4: K-ATP channel activation in response to complex I inhibition only in SN DA neurons.
Figure 5: Mitochondrial uncoupling controls differential K-ATP channel activation.
Figure 6: Selective rescue of SN DA neurons in Kir6.2−/− in a MPTP model of Parkinson disease.
Figure 7: In vitro responses to MPP+ and short-term in vivo responses to MPTP in Kir6.2+/+ and Kir6.2−/− mice.
Figure 8: Selective rescue of SN DA neurons in Kir6.2−/− weaver double mutant mice.

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Acknowledgements

We are grateful to F.M. Ashcroft and R. Veh for support. We thank the animal facility of Marburg University for animal care and J. Clark, D. Meyer, E. Naudascher and H. Neuhoff for technical support. This work was supported by the Parkinson's Disease Society, UK, the Medical Research Council, Bundesministerium fuer Bildung und Forschung (BMBF-NGFNII), Gemeinnützige Hertie Foundation, Royal Society, Deutsche Forschungsgemeinschaft (J.W.), and fellowships from New College, Oxford and the Royal Society (B.L.) and Exeter College, Oxford (J.R.).

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Authors and Affiliations

  1. Department of Physiology, Molecular Neurobiology, Marburg University Deutschhausstrasse 2, Marburg, 35037, Germany

    Birgit Liss & Olga Haeckel

  2. MRC Anatomical Neuropharmacology Unit, Oxford University, Mansfield Road, Oxford, OX1 3TH, UK

    Birgit Liss & Jochen Roeper

  3. University Laboratory of Physiology, Oxford University, Parks Road, Oxford, OX1 3PT, UK

    Birgit Liss

  4. Department of Physiology, Immunology, Marburg University, Deutschhausstrasse 2, Marburg, 35037, Germany

    Johannes Wildmann

  5. Cellular and Molecular Medicine, University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Kobe, 650-0017, Japan

    Takashi Miki & Susumu Seino

  6. Department of Physiology, Neurophysiology, Marburg University, Deutschhausstrasse 2, Marburg, 35037, Germany

    Jochen Roeper

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Correspondence to Birgit Liss.

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Liss, B., Haeckel, O., Wildmann, J. et al. K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons. Nat Neurosci 8, 1742–1751 (2005). https://doi.org/10.1038/nn1570

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