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The Human Serotonin 5-HT4 Receptor Regulates Secretion of Non-amyloidogenic Precursor Protein

AuthorsZugaza, José L.
Issue Date2001
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJournal of Biological Chemistry 276(48): 44881-4888 (2001)
AbstractThe serotonin 5-HT4 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-HT4 (h5-HT4) receptor stimulates the secretion of the non-amyloidogenic soluble form of the amyloid precursor protein (sAPPα). 5-HT enhanced the level of secreted sAPPα in a time- and dose-dependent manner in Chinese hamster ovary cells stably expressing the h5-HT4(e) receptor isoform. The increase was inhibited by the selective 5-HT4 receptor antagonist, GR113808. The 5-HT4 selective agonists, prucalopride and renzapride, also increased secreted sAPPα 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 sAPPα. 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 β-protein in Chinese hamster ovary cells transfected with the human APP695. Given the neuroprotective and enhancing memory effects of sAPPα, our results may open a new avenue for the treatment of Alzheimer's disease.
Identifiersdoi: 10.1074/jbc.M109008200
issn: 0021-9258
e-issn: 1083-351X
Appears in Collections:(IBMCC) Artículos
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