The prion protein and its paralogue Doppel affect calcium signaling in Chinese hamster ovary cells.
The function of the prion protein (PrP(c)), implicated in transmissible spongiform encephalopathies (TSEs), is largely unknown. We examined the possible influence of PrP(c) on Ca(2+) homeostasis, by analyzing local Ca(2+) fluctuations in cells transfected with PrP(c) and Ca(2+)-sensitive aequorin chimeras targeted to defined subcellular compartments. In agonist-stimulated cells, the presence of PrP(c) sharply increases the Ca(2+) concentration of subplasma membrane Ca(2+) domains, a feature that may explain the impairment of Ca(2+)-dependent neuronal excitability observed in TSEs. PrP(c) also limits Ca(2+) release from the endoplasmic reticulum and Ca(2+) uptake by mitochondria, thus rendering unlikely the triggering of cell death pathways. Instead, cells expressing Doppel, a PrP(c) paralogue, display opposite effects, which, however, are abolished by the coexpression of PrP(c). These findings are consistent with the functional interplay and antagonistic role attributed to the proteins, whereby PrP(c) protects, and Doppel sensitizes, cells toward stress conditions.
Brini
Marisa
M
Department of Biological Chemistry, University of Padova, CNR Institute of Neuroscience and CRIBI, 35121 Padova, Italy.
Miuzzo
Manuela
M
Pierobon
Nicola
N
Negro
Alessandro
A
Sorgato
Maria Catia
MC
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015153:Blotting, Western; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D018929:Cell Culture Techniques; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D003600:Cytosol / Q000737:chemistry; D003720:Densitometry; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D016257:Fura-2 / Q000494:pharmacology; D058851:GPI-Linked Proteins; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006706:Homeostasis; D007150:Immunohistochemistry; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018621:PrPC Proteins / Q000235:genetics / Q000494:pharmacology*; D011328:Prions / Q000235:genetics / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D002614:Chelating Agents; D058851:GPI-Linked Proteins; D018621:PrPC Proteins; D011328:Prions; C122036:Prnd protein, mouse; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate; D002118:Calcium; D016257:Fura-2