The GPI-anchored prion protein (PrPc) is involved in neurodegeneration, either through misfolding in the Transmissible Spongiform Encephalopathies (TSE), or as a mediator of the neurotoxicity of peptide oligomers in Alzheimer's Disease. PrPc has been attributed pleiotropic functions, and appears to scaffold a variety of cell surface signaling modules, for example through its binding to several neurotransmitter receptors. Here we used transfected HEK293 cells to test for an interaction of PrPc with purinergic receptor P2X4R. The prion protein bound P2X4R in both overlay and co-immunoprecipitation assays, and co-localized mostly intracellularly, but occasionaly at the cell surface in confocal micrographs. Functional PrPc:P2X4R interaction was tested by the uptake of a P2X4R-permeant compound, and by modulation of intracellular calcium. Unexpectedly, however, this interaction was traced to a selective effect of PrPc upon the content of co-transfected P2X4R. The results suggest a role of PrPc in proteostasis, dysfunctions of which may be involved in the pathogenesis of neurodegenerative diseases such as TSE and Alzheimer's Disease. (C) 2016 Elsevier Inc. All rights reserved.