A PrPC-caveolin-Lyn complex negatively controls neuronal GSK3β and serotonin 1B receptor
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 re...
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Veröffentlicht in: | Scientific reports 2014-05, Vol.4 (1), Article 4881 |
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Sprache: | eng |
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Zusammenfassung: | 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-HT
1B
R), 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-HT
1B
R activity, whose inhibition promotes an anxiogenic behavioural response. Collectively, our data unveil a new facet of PrP
C
signalling that strengthens neurotransmission. |
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ISSN: | 2045-2322 2045-2322 |
DOI: | 10.1038/srep04881 |