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

Abstract

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 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 transduced with genetically encoded Ca²⁺ probes and expressing, or not expressing, PrP^C Our investigation demonstrated that PrP^C downregulates Ca²⁺ 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 Ca²⁺ uptake in PrP-KO neurons than in their PrP^C-expressing counterpart. This was because the increased Ca²⁺ entry through iGluRs in PrP-KO neurons led to a parallel increase in Ca²⁺-induced Ca²⁺ release via ryanodine receptor channels. These data thus suggest that PrP^C takes part in the cell apparatus controlling Ca²⁺ homeostasis, and that PrP^C is involved in protecting neurons from toxic Ca²⁺ overloads.

Keywords: AMPA receptor; Ca2+ homeostasis; Ca2+-induced Ca2+ release; Glutamate; Mitochondria; Neuron; Prion protein.