Modulation of serotonergic receptor signaling and cross-talk by prion protein.
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.
Mouillet-Richard
Sophie
S
Différenciation cellulaire et prions, CNRS UPR 1983 Institut André Lwoff, 7 rue Guy Môquet, BP8, 94801 Villejuif Cedex, France. mouillet@vjf.cnrs.fr
Pietri
Mathéa
M
Schneider
Benoît
B
Vidal
Catherine
C
Mutel
Vincent
V
Launay
Jean-Marie
JM
Kellermann
Odile
O
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D051242:Caveolin 1; D022461:Caveolins / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010641:Phenotype; D018621:PrPC Proteins / Q000378:metabolism*; D011328:Prions / Q000378:metabolism*; D011485:Protein Binding; D011985:Receptors, Serotonin / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism
C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D018621:PrPC Proteins; D011328:Prions; D011985:Receptors, Serotonin; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D010738:Type C Phospholipases; D000262:Adenylyl Cyclases