Regulation of the amyloid precursor protein processing by the 5-HT4 receptor and small G proteins

Abstract

The serotonin 5-HT4 receptor mediates many physiological effects in the central nervous system. The recent molecular identification of 5-HT4 receptor isoforms with distinct C-terminal tails and the development of selective 5-HT4 receptor ligands have led to many important new insights into the signalling pathways and the physiological roles of these Gs protein-coupled-receptors in neurones. With respect to neurodegenerative disorders, it is suggested that 5-HT4 receptor agonists may represent a new avenue for the treatment of Alzheimer's disease. Because strong evidence supports beneficial effects of 5-HT4 receptor agonists in memory and learning, we investigated the potential involvement of the 5-HT4 receptor in the amyloid precursor protein processing (APP). Experiments were performed in different cell lines and primary culture of embryonic mouse cortical neurons. Activation of the human 5-HT4(e) receptor isoform stimulates the secretion of sAPPalpha. The increase was inhibited by selective 5-HT4 receptor antagonists, GR113808 and SB204070. Secretion of sAPPalpha induced by the h5-HT4(e) receptor seems not to be due to a general boost of the constitutive secretory pathway but rather to its specific effect on alpha secretases. In addition, we found that structural differences in the C-terminal tails of 5-HT4 receptor isoforms influence and contribute to the specificity of their functional response on APP processing. An interesting observation is that the effect of the 5-HT4 receptor on sAPPalpha release is independent of the protein kinase A (PKA). Indeed, the signalling pathway which couples the 5-HT4 receptor to sAPPalpha secretion involves small GTPases of the Ras and Rho families. Activation of the cAMP-regulated guanine nucleotide exchange factor (GEF), Epac stimulates alpha secretase activity through the small GTPases Rap1 and Rac in a cAMP-dependent but PKA-independent manner. These findings may open new avenues for the identification of new targets for the regulation of APP processing.