The prion protein regulates glutamate-mediated Ca entry and mitochondrial Ca accumulation in neurons.

The cellular prion protein (PrP) whose conformational misfolding leads to the production of deadly prions, has a still-unclarified cellular function despite decades of intensive research. Following our recent finding that PrP limits Ca entry via store-operated Ca channels in neurons, we investigated whether the protein could also control the activity of ionotropic glutamate receptors (iGluRs). To this end, we compared local Ca movements in primary cerebellar granule neurons and cortical neurons transduced with genetically encoded Ca probes and expressing, or not expressing, PrP Our investigation demonstrated that PrP downregulates Ca entry through each specific agonist-stimulated iGluR and after stimulation by glutamate. We found that, although PrP-knockout (KO) mitochondria were displaced from the plasma membrane, glutamate addition resulted in a higher mitochondrial Ca uptake in PrP-KO neurons than in their PrP-expressing counterpart. This was because the increased Ca entry through iGluRs in PrP-KO neurons led to a parallel increase in Ca-induced Ca release via ryanodine receptor channels. These data thus suggest that PrP takes part in the cell apparatus controlling Ca homeostasis, and that PrP is involved in protecting neurons from toxic Ca overloads.