KATP Channels Determine Which Dopaminergic Neurons Will Die

Science's STKE  13 Dec 2005:
Vol. 2005, Issue 314, pp. tw447
DOI: 10.1126/stke.3142005tw447

Liss et al. set out to understand why the dopaminergic (DA) neurons of the substantia nigra were selectively vulnerable to toxins that produce Parkinson's disease-like symptoms and dopaminergic cell death in mice. DA neurons of the substantia nigra or ventral tegmental area (VTA) were selectively labeled in brain slices from 3-month-old mice. All midbrain DA neurons exhibited ATP-regulated K+ current such that activation of the KATP channel in the brain slices with ATP-free solution hyperpolarized the membrane. This response was absent in slices from mice lacking the pore-forming subunit Kir6.2. All midbrain DA neurons expressed the mRNA for the SUR1 subunit of the KATP channel, so differences in susceptibility were not the result of either lack of the channel or differential expression of channel subunits. However, substantia nigra DA neurons exhibited greater magnitude KATP currents, which may be due to the increased abundance of the SUR1 mRNA relative to that present in the VTA DA neurons. Rotenone and 1-methyl-4-phenylpyridinium (MPP+) are mitochondrial respiratory complex I inhibitors that cause selective DA degeneration and increased reactive oxygen species (ROS) production. When applied with glucose, these agents alter ROS production without altering cellular metabolism. Application to brain slices of either of these complex I inhibitors in the presence of glucose resulted in the cessation of spontaneous activity and, ultimately, hyperpolarization of the membrane of striatal DA neurons, selectively. This response was absent in the slices from Kir6.2—/— mice. The difference in activation of the KATP channels in response to complex I inhibition appeared to involve the degree of mitochondrial uncoupling present in the different DA neurons. VTA DA neurons, which have greater abundance of the mRNA for the uncoupling protein UCP-2 than do the substantia nigra DA neurons, showed loss of firing and hyperpolarization in response to rotenone when the cells were pretreated with a low concentration of an uncoupling agent to cause a drop in ROS production. In contrast, pretreatment of substantia nigra DA neurons to cause mild uncoupling prevented hyperpolarization and loss of spontaneous activity in response to rotenone. The authors suggest that VTA DA neurons exist in a state of partial mitochondrial uncoupling and decreased ROS production that protects them by preventing activation of the KATP channel and loss of activity.

B. Liss, O. Haeckel, J. Wildmann, T. Miki, S. Seino, J. Roeper, K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons. Nat. Neurosci. 8, 1742-1751 (2005). [PubMed]