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K-ATP Channels and Their Role in the Survival of Nigral Dopaminergic Neurons

ATP-sensitive potassium (K-ATP) channels are present is numerous tissues including the brain. Their function has been best studied in the pancreatic B-islet cells that participate in the regulation of the blood glucose levels by the release of insulin. Attributable to this function, pharmacological blockage of K-ATP channels by compound class of sulfonylureas has been employed for the treatment of type 2 diabetes for more than 40 years because their deactivation stimulates insulin release from the pancreas. K-ATP channels are also present in several nerve cell populations that degenerate during the cause of Parkinson's disease, in particularly dopaminergic neurons in the substantia nigra. Their degeneration is causal to the debilitating motor defects that are observable in the patients.

Previous cell culture studies have shown that the channel is activated in neurotoxin based model systems for the disease and a deactivation has a protective effect on this nerve cell population. The funds provided by the Michael J. Fox Foundation will, therefore, be used to investigate in the living animal whether the pharmacological blockage of the channels can protect dopaminergic neurons in the substantia nigra from degeneration in MPTP intoxicated mice or in a genetic model for Parkinson's disease, the Engrailed mutants. These studies will evaluate whether K-ATP channels are suitable drug targets to prevent further degeneration in Parkinson's patients after diagnosis.

Final Outcome

Cell death involves a cascade of cellular signals and pathways and targeting these may have benefit for preventing neurodegeneration. Dr. Simon examined mice deficient for Sir1 (resulting in inactive K-ATP channels) and found that these mice are protected from MPTP toxicity. The K-ATP channel blocker glibenclamide also partially prevented cell loss in mice deficient for Engrailed, which results in a PD-like neurodegeneration.


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