1. 5-HT4 receptors constitutively promote the non-amyloidogenic pathway of APP cleavage and interact with ADAM10
- Author
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Maud Cochet, Philippe Marin, Aline Dumuis, Joël Bockaert, Stefan F. Lichtenthaler, Sylvie Claeysen, Elisabeth Cassier, Florence Gaven, Romain Donneger, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Supported by grants from CNRS, INSERM, the French Minister of Research (ANR Blanc 2006, to AD and SC, ANR Blanc 2012 'ADAMGUARD' to J.B.), the 'Fondation pour la Recherche Médicale' (FRM, to P.M.), the France Alzheimer association (to S.C.), the Soroptimist International (French Union, to S.C.), the Languedoc Roussillon region ('Chercheuse d’Avenir' 2012, to S.C.) and the competence network degenerative dementias (BMBF-KNDD, to S.F.L.). M.C. was a recipient of fellowships from the CNRS, the Languedoc Roussillon region and FRM. E.C. was supported by ANR Blanc 2006., ANR-06-BLAN-0087,GPCR dimers,Molecular and dynamic aspects of G-protein coupled receptor dimers functioning(2006), and ANR-12-BSV4-0008,ADAMGUARD,Les réseaux protéiques associés aux récepteurs 5 HT4 : gardes rapprochées du trafic de l'ADAM10 et de l'APP(2012)
- Subjects
Physiology ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,etiology [Alzheimer Disease] ,ADAM10 ,Stimulation ,Biochemistry ,Receptors, G-Protein-Coupled ,cytology [Cerebral Cortex] ,ADAM10 Protein ,Amyloid beta-Protein Precursor ,0302 clinical medicine ,metabolism [Amyloid beta-Protein Precursor] ,Amyloid precursor protein ,Cyclic AMP ,metabolism [Receptors, Serotonin, 5-HT4] ,physiology [Receptors, Serotonin, 5-HT4] ,Receptor ,Cerebral Cortex ,0303 health sciences ,General Medicine ,Alzheimer's disease ,pharmacology [Benzofurans] ,serotonin ,Neuroprotective Agents ,Alpha secretase ,ddc:540 ,metabolism [Cyclic AMP] ,Agonist ,medicine.drug_class ,ADAM10 protein, human ,Cognitive Neuroscience ,physiology [Receptors, G-Protein-Coupled] ,Biology ,Neuroprotection ,03 medical and health sciences ,Serotonin 5-HT4 Receptor Agonists ,Alzheimer Disease ,mental disorders ,medicine ,Humans ,physiology [Amyloid Precursor Protein Secretases] ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,030304 developmental biology ,G protein-coupled receptor ,Benzofurans ,pharmacology [Neuroprotective Agents] ,Membrane Proteins ,Cell Biology ,metabolism [Amyloid Precursor Protein Secretases] ,ADAM Proteins ,HEK293 Cells ,metabolism [ADAM Proteins] ,biology.protein ,Alpha-secretase ,Receptors, Serotonin, 5-HT4 ,sAPP alpha ,prucalopride ,Amyloid Precursor Protein Secretases ,metabolism [Membrane Proteins] ,pharmacology [Serotonin 5-HT4 Receptor Agonists] ,030217 neurology & neurosurgery - Abstract
International audience; In addition to the amyloidogenic pathway, amyloid precursor protein (APP) can be cleaved by α-secretases, producing soluble and neuroprotective APP alpha (sAPPα) (nonamyloidogenic pathway) and thus preventing the generation of pathogenic amyloid-β. However, the mechanisms regulating APP cleavage by α-secretases remain poorly understood. Here, we showed that expression of serotonin type 4 receptors (5-HT(4)Rs) constitutively (without agonist stimulation) induced APP cleavage by the α-secretase ADAM10 and the release of neuroprotective sAPPα in HEK-293 cells and cortical neurons. This effect was independent of cAMP production. Interestingly, we demonstrated that 5-HT(4) receptors physically interacted with the mature form of ADAM10. Stimulation of 5-HT(4) receptors by an agonist further increased sAPPα secretion, and this effect was mediated by cAMP/Epac signaling. These findings describe a new mechanism whereby a GPCR constitutively stimulates the cleavage of APP by α-secretase and promotes the nonamyloidogenic pathway of APP processing.
- Published
- 2012
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