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The cellular prion protein (PrP C ) 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 C limits Ca 2+ entry via store-operated Ca 2+ 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 2+ movements in primary cerebellar granule neurons and cortical neurons transduced with genetically encoded Ca 2+ probes and expressing, or not expressing, PrP C Our investigation demonstrated that PrP C downregulates Ca 2+ 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 2+ uptake in PrP-KO neurons than in their PrP C -expressing counterpart. This was because the increased Ca 2+ entry through iGluRs in PrP-KO neurons led to a parallel increase in Ca 2+ -induced Ca 2+ release via ryanodine receptor channels. These data thus suggest that PrP C takes part in the cell apparatus controlling Ca 2+ homeostasis, and that PrP C is involved in protecting neurons from toxic Ca 2+ overloads., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)