The human serotonin 5-HT 4 receptor regulates secretion of non Amyloidogenic Precursor Protein

Sylvain Robert (1, 2) , José Zugaza (2, 1, 3) , Rodolphe Fischmeister (2, 1) , Alain Gardier (2) , Frank Lezoualc'H (1, 2)

1 Cardiologie cellulaire et moléculaire
2 ISIT - Institut de signalisation et innovation thérapeutiques
3 U749 - Recepteurs et Signalisation des Interleukines

The serotonin 5-HT(4) receptor has recently gained a lot of attention for its functional roles in central processes such as memory and cognition. In this study, we show that activation of the human 5-HT(4) (h5-HT(4)) receptor stimulates the secretion of the non-amyloidogenic soluble form of the amyloid precursor protein (sAPPalpha). 5-HT enhanced the level of secreted sAPPalpha in a time- and dose-dependent manner in Chinese hamster ovary cells stably expressing the h5-HT(4(e)) receptor isoform. The increase was inhibited by the selective 5-HT(4) receptor antagonist, GR113808. The 5-HT(4) selective agonists, prucalopride and renzapride, also increased secreted sAPPalpha in IMR32 human neuroblastoma cells. The stimulatory effect of 5-HT was mimicked by forskolin, a direct activator of adenylyl cyclase, and 8-bromo-cAMP, a membrane-permeant cAMP analogue. On the contrary, inhibition of protein kinase A (PKA) by H89 potentiated the 5-HT-induced increase in both secreted and cellular sAPPalpha. This phenomenon involves a novel PKA-independent stimulatory process that overcomes a PKA-dependent inhibitory one. Finally, activation of the h5-HT(4(e)) receptor did not modify extracellular amyloid beta-protein in Chinese hamster ovary cells transfected with the human APP695. Given the neuroprotective and enhancing memory effects of sAPPalpha, our results may open a new avenue for the treatment of Alzheimer's disease.

Domaines: Neurobiologie

Sylvain Robert, José Zugaza, Rodolphe Fischmeister, Alain Gardier, Frank Lezoualc'H. The human serotonin 5-HT 4 receptor regulates secretion of non Amyloidogenic Precursor Protein. Journal of Biological Chemistry, 2001, 276 (48), pp.44881-44888. ⟨10.1074/jbc.M109008200⟩. ⟨hal-03610349⟩