Regulation of the amyloid precursor protein ectodomain shedding by the 5-HT4 receptor and Epac |
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| Authors: | Robert Sylvain Maillet Marjorie Morel Eric Launay Jean-Marie Fischmeister Rodolphe Mercken Luc Lezoualc'h Frank |
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| Affiliation: | Laboratoire de Cardiologie Cellulaire et Moléculaire, INSERM U-446, Faculté de Pharmacie, 5 rue J.-B. Clement, F-92296 Chatenay-Malabry, France. |
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| Abstract: | The serotonin 5-hydroxytryptamine (5-HT4) receptor is of potential interest for the treatment of Alzheimer's disease because it increases memory and learning. In this study, we investigated the effect of zinc metalloprotease inhibitors on the amyloid precursor protein (APP) processing induced by the serotonin 5-HT4 receptor in vitro. We show that secretion of the non-amyloidogenic form of APP, sAPPalpha induced by the 5-HT4(e) receptor isoform was not due to a general boost of the constitutive secretory pathway but rather to its specific effect on alpha-secretase activity. Although the h5-HT4(e) receptor increased IP3 production, inhibition of PKC did not modify its effect on sAPPalpha secretion. In addition, we found that alpha secretase activity is regulated by the cAMP-regulated guanine nucleotide exchange factor, Epac and the small GTPase Rac. |
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| Keywords: | ACh, acetylcholine AD, Alzheimer’s disease ADAM, a disintegrin and metalloprotease Aβ, amyloid β-peptide APP, amyloid precursor protein sAPPα, soluble form of the amyloid precursor protein FSK, forskolin GEF, guanine nucleotide exchange factor GPCRs, G protein-coupled receptors 5-HT, 5-hydroxytryptamine h5-HT4, human 5-HT4 receptor IP3, inositol 1,4,5-trisphosphate FCS, foetal calf serum CHO cells, Chinese hamster ovary cells SDS, sodium dodecyl sulfate PKC, protein kinase C SEAP, secreted placental alkaline phosphatase TACE, tumour necrosis factor α converting enzyme, ADAM17 TAPI, tumour necrosis factor-α protease inhibitor |
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