Cellular Prion Protein Signaling in Serotonergic Neuronal Cells

摘要

The cellular prion protein PrP~C is the normal counterpart of the scrapie prion protein PrP~(Sc), the main component of the infec tious agent of transmissible spongiform encephalopathies (TSEs). It is a ubiquitous cell-surface glycoprotein, abundantly expressed in neurons, which constitute the targets of TSE pathogenesis. Taking advantage of the 1C11 neuroectodermal cell line, endowed with the capacity to convert into 1C11~(5-HT) serotonergic or 1C11~(NE) noradrenergic neuronal cells, al lowed us to ascribe a signaling function to PrP~C. Antibody-mediated liga tion of PrP~C recruits transduction pathways, which involve nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species production and target the extracellular-regulated kinases ERK1/2. In fully differentiated cells only, these effectors are under the control of a PrP~C-caveolin-Fyn platform, located on neuritic extensions. In addition to its proper signaling activity, PrP~C modulates the agonist induced response of the three serotonergic G protein-coupled receptors present on the 1C11~(5-HT) differentiated cells. The impact of PrP~C liga tion on the receptor couplings depends on the receptor subtype and the pathway considered. The implementation of the PrP~C-caveolin complex again is mandatory for PrP~C to exert its action on 5-HT receptor sig naling. Our current data argue that PrP~C interferes with the intensities and/or dynamics of G protein activation by agonist-bound 5-HT recep tors. By mobilizing transduction cascades controlling the cellular redox state and the ERK1/2 kinases and by altering 5-HT receptor-mediated intracellular response, PrP~C takes part in the homeostasis of serotonergic neuronal cells. These findings may have implications for future research aiming at understanding the fate of serotonergic neurons in prion dis eases.