title: Amyloid β attenuates metabotropic zinc sensing receptor, mZnR/GPR39, dependent Ca2+, ERK1/2 and Clusterin signaling in neurons.
abstract: A hallmark of Alzheimer's disease is accumulation of amyloid beta (Aβ) deposits, which are associated with neuronal dysfunction, spine loss, and impaired Ca2+homeostasis. Amyloid beta (Aβ) binds to and is aggregated by Zn2+, a metal released from synaptic glutamatergic vesicles during neuronal activity. Synaptically released Zn2+activates a metabotropic Gq-coupled Zn2+-sensing receptor, mZnR/GPR39, and induces Ca2+-signaling in post-synaptic neurons. We examined if Aβ, as a Zn2+binding protein, regulates neuronal Zn2+-signaling mediated by mZnR/GPR39 using SHSY-5Y cells and cortical neurons from GPR39 wild-type and knockout mice. Following acute or chronic treatment with Aβ neuronal Zn2+-dependent Ca2+release via mZnR/GPR39 is significantly reduced. This impairment is overcome when excess Zn2+is applied, suggesting that impaired Ca2+-signaling results from Aβ binding of Zn2+. The Zn2+-dependent mZnR/GPR39 activation triggers phosphorylation of extracellular regulated kinase and up-regulates expression of the chaperone protein clusterin (Clu). Importantly, neuronal Zn2+-dependent extracellular regulated kinase1/2 phosphorylation and up-regulation of Clu are attenuated by silencing mZnR/GPR39 as well as by Aβ treatment. In contrast, Zn2+-dependent AKT phosphorylation is not mediated by mZnR/GPR39 and is not attenuated by Aβ treatment. Thus, Zn2+signaling via mZnR/GPR39 is distinctively disrupted by a critical pathological component of Alzheimer's disease. Synaptically released Zn2+activates a Zn2+-sensing receptor, mZnR/GPR39, and induces Ca2+-signaling, followed by ERK1/2 MAPK activation and up-regulation of clusterin. Amyloid beta (Aβ) binds to Zn2+thus forming oligomers that are a hallmark of Alzheimer's disease. We show that Aβ attenuates Zn2+-dependent Ca2+-responses, abolishes ERK1/2 activation and down-regulates clusterin expression. Thus, Zn2+signaling via mZnR/GPR39 is disrupted by Aβ, a critical pathological component of Alzheimer's disease.
authors: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors: Chen
authors: C
authors: Abramovitch-Dahan
authors: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors: Hila
authors: H
authors: Asraf
authors: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors: Milos
authors: M
authors: Bogdanovic
authors: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors: Israel
authors: I
authors: Sekler
authors: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
authors: Ashley I
authors: 0000-0001-8259-9069
authors: AI
authors: Bush
authors: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. hmichal@bgu.ac.il.
authors: Michal
authors: 0000-0003-1652-1989
authors: M
authors: Hershfinkel
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D051152:Clusterin / Q000187:drug effects*; D020868:Gene Silencing; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D061251:Primary Cell Culture; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics; D015032:Zinc / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D051152:Clusterin; C512928:GPR39 protein, mouse; D043562:Receptors, G-Protein-Coupled; C017800:zinc-binding protein; D051058:Oncogene Protein v-akt; D015032:Zinc
keywords: Ca2+-signaling; amyloid β; mZnR/GPR39; zinc