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Vol. 16, Issue 6, 2799-2808, June 2005

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The Prion Protein and Its Paralogue Doppel Affect Calcium Signaling in Chinese Hamster Ovary Cells

Marisa Brini ^* , Manuela Miuzzo ^*, Nicola Pierobon ^*, Alessandro Negro ^* , and Maria Catia Sorgato ^*

^* Department of Biological Chemistry, University of Padova, CNR Institute of Neuroscience and CRIBI, 35121 Padova, Italy; Department of Experimental Veterinary Sciences, University of Padova, 35020 Legnaro-Padova, Italy

Submitted October 21, 2004; Revised March 2, 2005; Accepted March 16, 2005
Monitoring Editor: Thomas Fox

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 Ca²⁺ homeostasis, by analyzing local Ca²⁺ fluctuations in cells transfected with PrP^c and Ca²⁺-sensitive aequorin chimeras targeted to defined subcellular compartments. In agonist-stimulated cells, the presence of PrP^c sharply increases the Ca²⁺ concentration of subplasma membrane Ca²⁺ domains, a feature that may explain the impairment of Ca²⁺-dependent neuronal excitability observed in TSEs. PrP^c also limits Ca²⁺ release from the endoplasmic reticulum and Ca²⁺ 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.

Abbreviations used: AEQ, aequorin; cytAEQ, erAEQ, mtAEQ, and pmAEQ, aequorin targeted to the cytosol, the endoplasmic reticulum, the mitochondrial matrix and the plasma membrane, respectively; tBuBHQ, 2,5-di-(tert-butyl)-1,4-benzohydroquinone; CCE, capacitative Ca²⁺ entry; Dpl, Doppel; Dpl_rec, recombinant Doppel; ER, endoplasmic reticulum; GFP, green fluorescent protein; GPI, glycosylphosphatidylinositol; InsP₃, inositol-1,4,5-triphosphate; mAb, monoclonal antibody; PrP^c, cellular prion protein; PrP^Sc, pathological isoform of prion protein; PrP_rec, recombinant prion protein; SERCA, sarco(endo)plasmic reticulum Ca²⁺-ATPase; SOCC, store-operated Ca²⁺ channels; TSE, transmissible spongiform encephalopathy.

Address correspondence to: Maria Catia Sorgato (catia.sorgato{at}unipd.it).

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