NR AVWY
AU Krebs,B.; Wiebelitz,A.; Balitzki-Korte,B.; Vassallo,N.; Paluch,S.; Mitteregger,G.; Onodera,T.; Kretzschmar,H.A.; Herms,J.W.
TI Cellular prion protein modulates the intracellular calcium response to hydrogen peroxide
QU Journal of Neurochemistry 2007 Jan; 100(2): 358-67
PT journal article; research support, non-u.s. gov't
AB The physiological function of the cellular prion protein (PrPc) is still under intense investigation. It has been suggested that PrPc has a protective role in neuronal cells, particularly against environmental stress caused by reactive oxygen species (ROS). Here we analysed the acute effect of a major ROS, hydrogen peroxide (H(2)O(2)), on intracellular calcium homeostasis in cultured cerebellar granule cells and immortalized hippocampal neuronal cells. Both neuronal cell culture models showed that the rise in intracellular calcium following application of H(2)O(2) was strongly dependent on the presence of PrPc. Moreover, the N-terminal octapeptide repeats of PrPc were required for this effect, because neuronal cells expressing a PrPc lacking the N-terminus resembled the PrPc-deficient phenotype. Neurones deficient of fyn kinase, or pharmacological inhibition of fyn, also abrogated the calcium response to H(2)O(2) treatment, indicating that fyn activation is a critical step within the PrPc signalling cascade. Finally, we identified a possible role of this PrPc signalling pathway in the neuroprotective response of PrPc to oxidative stress. In conclusion, we put forward the hypothesis that PrPc functions as a sensor for H(2)O(2), thereby activating a protective signalling cascade involving fyn kinase that leads to calcium release from intracellular stores.
MH Animals; Animals, Newborn; Blotting, Western/methods; Calcium/*metabolism; Cell Survival/drug effects; Cells, Cultured; Cerebellum/cytology; Complement C4/deficiency; Diagnostic Imaging/methods; Dose-Response Relationship, Drug; Endoplasmic Reticulum/drug effects/metabolism; Gene Expression/drug effects/physiology; Hydrogen Peroxide/*pharmacology; Intracellular Fluid/*drug effects/metabolism; Mice; Mice, Knockout; Neurons/*cytology; Oxidants/*pharmacology; Potassium Chloride/pharmacology; Prions/genetics/*metabolism; Proto-Oncogene Proteins c-fyn/deficiency; Time Factors
AD Centre for Neuropathology and Prion Research, Ludwig-Maximilians-University of Munich, Munich, Germany.
SP englisch
PO England