title: A PrP(C)-caveolin-Lyn complex negatively controls neuronal GSK3β and serotonin 1B receptor.
abstract: The cellular prion protein, PrP(C), is a glycosylphosphatidylinositol-anchored protein, abundant in lipid rafts and highly expressed in the brain. While PrP(C) is much studied for its involvement under its abnormal PrP(Sc) isoform in Transmissible Spongiform Encephalopathies, its physiological role remains unclear. Here, we report that GSK3β, a multifunctional kinase whose inhibition is neuroprotective, is a downstream target of PrP(C) signalling in serotonergic neuronal cells. We show that the PrP(C)-dependent inactivation of GSK3β is relayed by a caveolin-Lyn platform located on neuronal cell bodies. Furthermore, the coupling of PrP(C) to GSK3β potentiates serotonergic signalling by altering the distribution and activity of the serotonin 1B receptor (5-HT1BR), a receptor that limits neurotransmitter release. In vivo, our data reveal an increased GSK3β kinase activity in PrP-deficient mouse brain, as well as sustained 5-HT1BR activity, whose inhibition promotes an anxiogenic behavioural response. Collectively, our data unveil a new facet of PrP(C) signalling that strengthens neurotransmission.
authors.affiliation: 1] INSERM UMR-S1124, 75006 Paris France [2] Université Paris Descartes, Sorbonne Paris Cité, UMR-S1124, 75006 Paris France [3] Université Paris Sud 11, ED419 Biosigne, 91400 Orsay, France [4].
authors.forename: Julia
authors.initials: J
authors.lastname: Hernandez-Rapp
authors.affiliation: 1] INSERM UMR-S1124, 75006 Paris France [2] Université Paris Descartes, Sorbonne Paris Cité, UMR-S1124, 75006 Paris France [3].
authors.forename: Séverine
authors.initials: S
authors.lastname: Martin-Lannerée
authors.affiliation: 1] INSERM UMR-S1124, 75006 Paris France [2] Université Paris Descartes, Sorbonne Paris Cité, UMR-S1124, 75006 Paris France [3].
authors.forename: Théo Z
authors.initials: TZ
authors.lastname: Hirsch
authors.affiliation: 1] INSERM UMR-S1124, 75006 Paris France [2] Université Paris Descartes, Sorbonne Paris Cité, UMR-S1124, 75006 Paris France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Pradines
authors.affiliation: 1] INSERM UMR-S1124, 75006 Paris France [2] Université Paris Descartes, Sorbonne Paris Cité, UMR-S1124, 75006 Paris France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Alleaume-Butaux
authors.affiliation: 1] INSERM UMR-S1124, 75006 Paris France [2] Université Paris Descartes, Sorbonne Paris Cité, UMR-S1124, 75006 Paris France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Schneider
authors.affiliation: 1] INSERM UMR-S1124, 75006 Paris France [2] Université Paris Descartes, Sorbonne Paris Cité, UMR-S1124, 75006 Paris France.
authors.forename: Anne
authors.initials: A
authors.lastname: Baudry
authors.affiliation: 1] AP-HP Service de Biochimie, Fondation FondaMental, INSERM U942 Hôpital Lariboisière, 75010 Paris, France [2] Pharma Research Department, F. Hoffmann-La-Roche Ltd., CH-4070 Basel, Switzerland.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Launay
authors.affiliation: 1] INSERM UMR-S1124, 75006 Paris France [2] Université Paris Descartes, Sorbonne Paris Cité, UMR-S1124, 75006 Paris France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Mouillet-Richard
mesh_terms: D000818:Animals; D022461:Caveolins / Q000378:metabolism*; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism; D011328:Prions / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D022461:Caveolins; D011328:Prions; D044302:Receptor, Serotonin, 5-HT1B; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3