Cellular Prion Protein Signaling in Serotonergic Neuronal Cells
The cellular prion protein PrPC is the normal counterpart of the scrapie prion protein PrPSc, the main component of the infectious 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 1C115-HT serotonergic or 1C11NE noradrenergic neuronal cells, allowed us to ascribe a signaling function to PrPC. Antibody-mediated ligation of PrPC 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 PrPC-caveolin-Fyn platform, located on neuritic extensions. In addition to its proper signaling activity, PrPC modulates the agonist-induced response of the three serotonergic G proteincoupled receptors present on the 1C115-HT differentiated cells. The impact of PrPC ligation on the receptor couplings depends on the receptor subtype and the pathway considered. The implementation of the PrPC-caveolin complex again is mandatory for PrPC to exert its action on 5-HT receptor signaling. Our current data argue that PrPC interferes with the intensities and/or dynamics of G protein activation by agonist-bound 5-HT receptors. By mobilizing transduction cascades controlling the cellular redox state and the ERK1/2 kinases and by altering 5-HT receptor-mediated intracellular response, PrPC 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 diseases
prion protein serotonergic neurons gpcr caveolin