Among the different types of K+ channels (109,110) and varieties of the inward rectifier potassium channel family (111), activation of a specific subtype of inwardly rectifying K-ATP channel in the dopaminergic neurons of the SNpc has been suggested to contribute to the selective vulnerability to degeneration of SNpc dopamine neurons rather than the VTA neurons (112). K-ATP channels play a very important role as a sensor that link cellular metabolism to electrical activity of the cell. K-ATP channels are distributed in the muscle, brain, and pancreas (113). Pancreatic K-ATP channels play a role in insulin secretion and functional disruption of K-ATP channels due to mutations of the subunits or other causes have been shown to be responsible for either hypersecretion of insulin or inducing diabetes (114-118).
K-ATP channels are made of two different proteins, namely the ion pore forming subunit Kir6.2 and the regulatory sulfonylurea receptor (SUR1) subunit. Kir6.2 has two transmembrane domains and consists of an ATP-binding region. The SUR1 subunit has two six-helix transmembrane domains, consisting of a site that has a high affinity to bind to sulfonylurea, the antidiabetic drug, and Mg++. Four of Kir6.2 and four of SUR1 form the K-ATP channel. The architecture of K-ATP channels has similarities to that of K-ATP channels in the pancreas (114).
The mRNA for Kir6.2 is distributed widely in the brain, but very densely in the ventromedial and the paraventricular nuclei of the hypothalamus and also with moderate intensity in the mesencephalic dopamine neurons. K-ATP channels are expressed in all the mesencephalic dopamine neurons and play a significant role in the excitability and the distinctive electrophysiological properties of VTA and SNpc dopamine neurons (112). Among the SUR subunits, SUR1 mRNA is found in dopamine neurons of both VTA and SNpc, but SUR2B is found in less than 5% of dopamine neurons suggesting that SUR1 plays a major role in these mesencephalic dopamine neurons (73,112). The level of SUR1 mRNA expression in SNpc dopamine neurons is two-fold higher than that of the VTA dopamine neurons. Although the majority of the dopamine neurons of the midbrain express SUR1 mRNA, TH-positive SUR1 negative neurons are about 36% in the SNpc and 41% in the VTA (73).
MPP+ and rotenone inhibit complex I of the electron transport chain throughout the brain and, possibly, in all tissues of the body; however, the various molecular factors that contribute to the selective vulnerability of dopamine neurons of the SNpc to neurodegeneration but not the VTA dopamine neurons are unknown.
Among the mesencephalic dopamine neurons, the TH- and SUR1-immunoreactive neurons of the SNpc appear to be specifically sensitive to the neu-rotoxins MPP+ and rotenone. MPP+ and rotenone models of PD in mice demonstrate that the K-ATP channels of the SNpc but not the VTA are selectively activated. MPP+ and rotenone induce complex I inhibition, increase production of ROS, decrease levels of ATP, and increase oxidative stress and dysfunction of the ubiquitin-proteaso-mal system (UPS). Complex I inhibition alone as well as decreased ATP levels and oxidative stress can activate K-ATP channel selectively. MPTP- and rotenone-
induced neurotoxicity requires the presence of active K-ATP channels, since genetic inactivation of the Kir6.2 subunit of the K-ATP channels protects the SNpc neurons from degeneration in chronic MPTP models of PD in mice, as well as in weaver mutants (73,107,112).
Preferential activation of the K-ATP channels in the SNpc dopamine neurons and not the K-ATP channels of the VTA dopamine neurons may be a factor that is responsible for the early degeneration of the SNpc dopamine but not the VTA dopamine neurons. The presence of functioning K-ATP channels along with preferential uncoupling of mitochondria due to decreased levels of expression of UCP2 in the SNpc but not in the VTA may contribute to the selective vulnerability of SNpc dopamine neurons to neurodegeneration (73).
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