Cellular prion protein modulates the intracellular calcium response to hydrogen peroxide.
The physiological function of the cellular prion protein (PrP(C)) is still under intense investigation. It has been suggested that PrP(C) 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 PrP(C). Moreover, the N-terminal octapeptide repeats of PrP(C) were required for this effect, because neuronal cells expressing a PrP(C) lacking the N-terminus resembled the PrP(C)-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 PrP(C) signalling cascade. Finally, we identified a possible role of this PrP(C) signalling pathway in the neuroprotective response of PrP(C) to oxidative stress. In conclusion, we put forward the hypothesis that PrP(C) 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.
Krebs
Bjarne
B
Centre for Neuropathology and Prion Research, Ludwig-Maximilians-University of Munich, Munich, Germany.
Wiebelitz
Antje
A
Balitzki-Korte
Beate
B
Vassallo
Neville
N
Paluch
Sandra
S
Mitteregger
Gerda
G
Onodera
Takashi
T
Kretzschmar
Hans A
HA
Herms
Jochen
J
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D003181:Complement C4 / Q000172:deficiency; D003952:Diagnostic Imaging / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology*; D016877:Oxidants / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn / Q000172:deficiency; D013997:Time Factors
C016759:C4b protein, mouse; D003181:Complement C4; D016877:Oxidants; D011328:Prions; D011189:Potassium Chloride; D006861:Hydrogen Peroxide; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D002118:Calcium