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

• Published in: Journal of neurochemistry 2016-10, Vol.139 (2), p.221-233
• Main Authors: Abramovitch‐Dahan, Chen, Asraf, Hila, Bogdanovic, Milos, Sekler, Israel, Bush, Ashley I., Hershfinkel, Michal
• Format: Article
• Language: English
• Subjects: amyloid β; Ca2+‐signaling; mZnR/GPR39; zinc
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.13760

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. 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