Distinct functional effects of human 5-HT4 receptor isoforms on β-amyloid secretion

Background: The serotonin 5-HT4 receptor is of potential interest for the treatment of Alzheimer's disease because it increases memory and learning and influences amyloid precursor protein (APP) processing. Several 5-HT4 receptor isoforms have been cloned in humans. They all belong to the G-protein-coupled receptor superfamily and differ in composition and length of their amino acid intracellular C-terminal sequence. At present, it is still unknown whether 5-HT4 receptor isoforms may have distinct effects on APP processing. Objective: In this study, we investigated the effect of an ultrashort isoform of the human 5-HT4 receptor (2 amino acids after the splicing site), the 5-HT4(d) receptor isoform (h5HT(4(d))), on APP processing in Chinese hamster ovary cells (CHO cells). Methods: Non-amyloidogenic soluble sAPP alpha was determined by immunoblot and P-amyloid peptides (A beta(1-40) and A beta(1-42)) were assayed by ELISA in CHO cells stably expressing h5-HT4(d) and transiently transfected with human APP(695). Results: We show here that activation of h5-HT4(d) strongly stimulates the release of sAPP alpha and concomitantly decreases extracellular A beta peptides. These data contrast with our previous findings showing that the h5-HT4(e/g) receptor isoform, which has 20 amino acids after the splicing site, did not influence A beta secretion. Conclusion: We conclude that C-terminal tails of 5-HT4 receptor isoforms may influence their functional effect on A beta secretion and that the pathways regulating either beta- or gamma-secretase may be differentially controlled by 5-HT4 receptor isoforms. (c) 2008 S. Karger AG, Basel.