Amyloid β attenuates metabotropic zinc sensing receptor, mZnR/GPR39, dependent Ca2+, ERK1/2 and Clusterin signaling in neurons

Chen Abramovitch-Dahan, Hila Asraf, Milos Bogdanovic, Israel Sekler, Ashley I. Bush, Michal Hershfinkel

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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. (Figure presented.) 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.

Original languageEnglish
Pages (from-to)221-233
Number of pages13
JournalJournal of Neurochemistry
DOIs
StatePublished - 1 Oct 2016

Keywords

  • Ca-signaling
  • amyloid β
  • mZnR/GPR39
  • zinc

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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