title: Calcium regulates the interaction of amyloid precursor protein with Homer3 protein.
abstract: Ca(2+) dysregulation is an important factor implicated in Alzheimer's disease pathogenesis. The mechanisms mediating the reciprocal regulation of Ca(2+) homeostasis and amyloid precursor protein (APP) metabolism, function, and protein interactions are not well known. We have previously shown that APP interacts with Homer proteins, which inhibit APP processing toward amyloid-β. In this study, we investigated the effect of Ca(2+) homeostasis alterations on APP/Homer3 interaction. Influx of extracellular Ca(2+) upon treatment of HEK293 cells with the ionophore A23187 or addition of extracellular Ca(2+) in cells starved of calcium specifically reduced APP/Homer3 but not APP/X11a interaction. Endoplasmic reticulum Ca(2+) store depletion by thapsigargin followed by store-operated calcium entry also decreased the interaction. Interestingly, application of a phospholipase C stimulator, which causes inositol 1,4,5-trisphosphate-induced endoplasmic reticulum Ca(2+) release, caused dissociation of APP/Homer3 complex. In human neuroblastoma cells, membrane depolarization also disrupted the interaction. This is the first study showing that changes in Ca(2+) homeostasis affect APP protein interactions. Our results suggest that Ca(2+) and Homers play a significant role in the development of Alzheimer's disease pathology.
authors.affiliation: Division of Animal and Human Physiology, Department of Biology, National and Kapodistrian University of Athens, Ilisia, Athens, Greece.
authors.forename: Elli
authors.initials: E
authors.lastname: Kyratzi
authors.affiliation: Division of Animal and Human Physiology, Department of Biology, National and Kapodistrian University of Athens, Ilisia, Athens, Greece. Electronic address: efthis@biol.uoa.gr.
authors.forename: Spiros
authors.initials: S
authors.lastname: Efthimiopoulos
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D061207:Calcium Ionophores / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D000072233:Homer Scaffolding Proteins; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D009447:Neuroblastoma; D011485:Protein Binding; D019284:Thapsigargin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D016564:Amyloid beta-Protein Precursor; D061207:Calcium Ionophores; D002352:Carrier Proteins; C000606616:HOMER3 protein, human; D000072233:Homer Scaffolding Proteins; D000001:Calcimycin; D019284:Thapsigargin; D002118:Calcium
keywords: Alzheimer's disease; Amyloid precursor protein (APP); Calcium homeostasis; Homer