The unclear function of PrPC hampers elucidation of the mechanism of prion disease, and the development of suitable therapies. A wealth of evidence has suggested that PrPC function is beneficial to the cell, ranging from cell signaling to differentiation and protection against oxidative injury. We have undertaken PrPC functional analysis using paradigms novel to the prion field, composed of ex vivo, in vivo and in vitro models derived from WT, PrP-KO, and PrP-OE congenic mice. Because among extra-neural tissues muscles have been linked to PrPC patho-physiology, we have exploited an ex vivo model of oxidative challenge, i.e. isolated hearts subjected to ischemia/reperfusion, and an in vivo paradigm given by the degeneration/regeneration of the Tibialis anterior skeletal muscle. Using such acute stress protocols, we have assessed the involvement of PrPC in the cell defence against oxidative injury and in adult tissue morphogenesis, respectively. Several reports have indicated that PrPC may be related to Ca2+ homeostasis. On this basis we have monitored local Ca2+ fluxes in cerebellar granule cells - derived from the above murine lines - using recombinant Ca2+-sensitive photo-probes. Our results indicate that in the absence of PrPC modifications of Ca2+ fluxes occur in the cytosolic domain beneath the plasma membrane, in the lumen of the endoplasmic reticulum and in the mitochondrial matrix. All these results indicate a close link between PrPC and Ca2+ fluctuations, thereby raising the possibility that Ca2+ could be the means by which PrPC mediates cell signaling pathways.