Distinct functional effects of human 5-HT4 receptor isoforms on beta-amyloid secretion.
BACKGROUND
The serotonin 5-HT(4) 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-HT(4) 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-HT(4) 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-HT(4) receptor (2 amino acids after the splicing site), the 5-HT(4(d)) receptor isoform (h5-HT(4(d))), on APP processing in Chinese hamster ovary cells (CHO cells).


METHODS
Non-amyloidogenic soluble sAPPalpha was determined by immunoblot and beta-amyloid peptides (Abeta(1-40) and Abeta(1-42)) were assayed by ELISA in CHO cells stably expressing h5-HT(4(d)) and transiently transfected with human APP(695).


RESULTS
We show here that activation of h5-HT(4(d)) strongly stimulates the release of sAPPalpha and concomitantly decreases extracellular Abeta peptides. These data contrast with our previous findings showing that the h5-HT(4(e/g)) receptor isoform, which has 20 amino acids after the splicing site, did not influence Abeta secretion.


CONCLUSIONS
We conclude that C-terminal tails of 5-HT(4) receptor isoforms may influence their functional effect on Abeta secretion and that the pathways regulating either beta- or gamma-secretase may be differentially controlled by 5-HT(4) receptor isoforms.
Robert
Sylvain J
SJ
INSERM, U769 and IFR141, Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France.
Lezoualc'h
Frank
F
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D000818:Animals; D006801:Humans; D009434:Neural Pathways / Q000502:physiology; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D044422:Receptors, Serotonin, 5-HT4 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D020033:Protein Isoforms; D044422:Receptors, Serotonin, 5-HT4; D053829:Amyloid Precursor Protein Secretases