NR ARSC
AU Mouillet-Richard,S.; Pietri,M.; Schneider,B.; Vidal,C.; Mutel,V.; Launay,J.M.; Kellermann,O.
TI Modulation of serotonergic receptor signaling and cross-talk by prion protein
QU The Journal of Biological Chemistry 2005 Feb 11; 280(6): 4592-601
PT journal article
AB The inducible serotonergic 1C115-HT cell line expresses a defined set of serotonergic receptors of the 5-HT2B, 5-HT1B/D, and 5-HT2A subtypes, which sustain a regulation of serotonergic associated functions through G-protein-dependent signaling. 1C115-HT cells have been instrumental to assign a signaling function to the cellular prion protein PrPc. Here, we establish that antibody-mediated ligation of PrPc concomitant to agonist stimulation of 5-HT receptors modulates the couplings of all three serotonergic receptors present on 1C115-HT cells. Specific impacts of PrP antibodies were monitored depending on the receptor and pathway considered. PrPc ligation selectively cancels the 5-HT2A-PLC response, decreases the 5-HT1B/D negative coupling to adenylate cyclase, and potentiates the 5-HT2B-PLA2 coupling. As a result, PrPc ligation disturbs the functional interactions occurring between the signaling pathways of the three receptor subtypes. In 1C115-HT cells, antagonizing cross-talks arising from 5-HT2B and 5-HT2A receptors control the 5-HT1B/D function. PrPc ligation reinforces the negative regulation exerted by 5-HT2B on 5-HT1B/D receptors. On the other hand it abrogates the blocking action of 5-HT2A on the regulatory loop linking 5-HT1B/D receptors. We propose that the ligation of PrPc affects the potency or dynamics of G-protein activation by agonist-bound serotonergic receptors. Finally, the PrPc-dependent modulation of 5-HT receptor couplings is restricted to 1C115-HT cells expressing a complete serotonergic phenotype. It critically involves a PrPc-caveolin platform implemented on the neurites of 1C115-HT cells during differentiation. Our findings define PrPc as a modulator of 5-HT receptor coupling to G-proteins and thereby as a protagonist contributing to the homeostasis of serotonergic neurons. They provide a foundation for uncovering the impact of prion infection on serotonergic functions.
MH Adenylate Cyclase/metabolism; Animals; Caveolins/metabolism; Cell Differentiation; Cell Line; Cell Membrane/metabolism; Cyclic AMP/metabolism; Dose-Response Relationship, Drug; Gene Expression Regulation; Mice; Models, Biological; Neurons/metabolism; Nitric-Oxide Synthase/metabolism; Phenotype; Phospholipase C/metabolism; PrPc Proteins/*metabolism; Prions/*metabolism; Protein Binding; Receptors, Serotonin/*metabolism; Research Support, Non-U.S. Gov't; *Signal Transduction; Time Factors
AD Differenciation cellulaire et prions, CNRS UPR 1983 Institut Andre Lwoff, 7 rue Guy Moquet, BP8, 94801 Villejuif Cedex, France. mouillet@vjf.cnrs.fr
SP englisch
PO USA