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

Abstract

The 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.