Modulation of serotonergic receptor signaling and cross-talk by prion protein

The inducible serotonergic 1C11^5-HT cell line expresses a defined set of serotonergic receptors of the 5-HT_2B, 5-HT _1B/D, and 5-HT_2A subtypes, which sustain a regulation of serotonergic associated functions through G-protein-dependent signaling. 1C11^5-HT cells have been instrumental to assign a signaling function to the cellular prion protein PrP^c. Here, we establish that antibody-mediated ligation of PrP^c concomitant to agonist stimulation of 5-HT receptors modulates the couplings of all three serotonergic receptors present on 1C11^5-HT cells. Specific impacts of PrP antibodies were monitored depending on the receptor and pathway considered. PrP^c ligation selectively cancels the 5-HT_2A-PLC response, decreases the 5-HT_1B/D negative coupling to adenylate cyclase, and potentiates the 5-HT_2B-PLA2 coupling. As a result, PrP^c ligation disturbs the functional interactions occurring between the signaling pathways of the three receptor subtypes. In 1C11^5-HT cells, antagonizing cross-talks arising from 5-HT_2B and 5-HT_2A receptors control the 5-HT_1B/D function. PrP^c ligation reinforces the negative regulation exerted by 5-HT_2B on 5-HT_1B/D receptors. On the other hand it abrogates the blocking action of 5-HT_2A on the regulatory loop linking 5-HT_2B and 5-HT_1B/D receptors. We propose that the ligation of PrP^c affects the potency or dynamics of G-protein activation by agonist-bound serotonergic receptors. Finally, the PrP^c-dependent modulation of 5-HT receptor couplings is restricted to 1C11^5-HT cells expressing a complete serotonergic phenotype. It critically involves a PrP^c-caveolin platform implemented on the neurites of 1C11^5-HT cells during differentiation. Our findings define PrP^c 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.