The prion protein regulates glutamate-mediated Ca2+ entry and mitochondrial Ca2+ accumulation in neurons

Abstract

The prion protein, PrPC, whose conformational misfolding originates deadly prions, has a still unclarified cellular function despite decades of intensive research. Following our recent finding that PrPC limits Ca2+ entry via store-operated Ca2+ channels in neurons, we investigated whether the protein could also control the activity of ionotropic glutamate receptors (iGluRs). To this end, we compared local Ca2+ movements in primary cerebellar granule neurons and cortical neurons, expressing, or not, PrPC, transduced with genetically encoded Ca2+ probes. Our investigation demonstrated that PrPC downregulates Ca2+ entry through each specific agonist-stimulated iGluR or after stimulation by glutamate. In spite of the displacement from the plasma membrane of PrP-KO mitochondria, glutamate addition resulted in a higher mitochondrial Ca2+ uptake by PrP-KO neurons compared to the PrPC-expressing counterpart, because the increased Ca2+ entry through iGluRs in PrP-KO neurons reflected in a parallel increase of Ca2+-induced Ca2+-release via ryanodine receptor channels. These data thus suggest that PrPC takes part in the cell apparatus controlling Ca2+ homeostasis, and that PrPC is involved in protecting neurons from toxic Ca2+ overloads.