The human serotonin 5-HT4 receptor regulates secretion of non-amyloidogenic precursor protein.
The serotonin 5-HT(4) 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-HT(4) (h5-HT(4)) receptor stimulates the secretion of the non-amyloidogenic soluble form of the amyloid precursor protein (sAPPalpha). 5-HT enhanced the level of secreted sAPPalpha in a time- and dose-dependent manner in Chinese hamster ovary cells stably expressing the h5-HT(4(e)) receptor isoform. The increase was inhibited by the selective 5-HT(4) receptor antagonist, GR113808. The 5-HT(4) selective agonists, prucalopride and renzapride, also increased secreted sAPPalpha 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 sAPPalpha. 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 beta-protein in Chinese hamster ovary cells transfected with the human APP695. Given the neuroprotective and enhancing memory effects of sAPPalpha, our results may open a new avenue for the treatment of Alzheimer's disease.
Robert
S J
SJ
Laboratoire de Cardiologie Cellulaire et Moléculaire, INSERM U-446, Université Paris-Sud, Faculté de Pharmacie, F-92296 Châtenay-Malabry, France.
Zugaza
J L
JL
Fischmeister
R
R
Gardier
A M
AM
Lezoualc'h
F
F
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000544:Alzheimer Disease / Q000628:therapy; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D016466:CHO Cells; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008024:Ligands; D008568:Memory; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D020033:Protein Isoforms; D011863:Radioimmunoassay; D011985:Receptors, Serotonin / Q000378:metabolism*; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D016564:Amyloid beta-Protein Precursor; D001549:Benzamides; D001572:Benzofurans; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007211:Indoles; D008024:Ligands; D020033:Protein Isoforms; D011985:Receptors, Serotonin; D013449:Sulfonamides; C406662:prucalopride; D044422:Receptors, Serotonin, 5-HT4; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D012701:Serotonin; C053006:renzapride; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; C082871:GR 113808