Amyloid β attenuates metabotropic zinc sensing receptor, mZnR/GPR39, dependent Ca2+, ERK1/2 and Clusterin signaling in neurons
Amyloid β attenuates metabotropic zinc sensing receptor, mZnR/GPR39, dependent Ca2+, ERK1/2 and Clusterin signaling in neurons
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DOI：
10.1111/jnc.13760
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发表时间：
2016-10-01
影响因子：
4.7
通讯作者：
Hershfinkel, Michal
中科院分区：
文献类型：
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作者：
Abramovitch-Dahan, Chen;Asraf, Hila;Hershfinkel, Michal
阿尔茨海默病的一个特征是淀粉样β蛋白(Aβ)沉积的积累，这与神经元功能障碍、脊柱丢失和钙离子稳态受损有关。淀粉样β蛋白(Aβ)与锌离子结合并被锌离子聚集，锌离子是突触谷氨酸能小泡在神经元活动过程中释放的一种金属。突触释放的锌离子激活代谢性Gq偶联的锌离子敏感受体mZnR/GPR39，并在突触后神经元诱导钙信号转导。我们使用SHSY-5Y细胞和GPR39野生型和基因敲除小鼠的皮质神经元，研究了Aβ作为锌离子结合蛋白是否调节mZnR/GPR39介导的神经元锌信号转导。经急性或慢性Aβ处理后，神经元通过mZnR/GPR39的依赖锌离子的钙释放显著减少。当施加过量的锌离子时，这种损伤被克服，这表明钙信号的受损是由于锌离子的Aβ结合所致。依赖于锌离子的mZnR/GPR39的激活触发了胞外调节蛋白的磷酸化，并上调了伴侣蛋白Clusterin(Clu)的表达。重要的是，沉默mZnR/GPR39和Aβ处理可减弱依赖于细胞外锌离子的细胞外调节激酶1/2的磷酸化和Clu的上调。相反，依赖于锌离子的AKT磷酸化不受mZnR/GPR39的调节，也不被Aβ处理所减弱。因此，通过mZnR/GPR39的锌离子信号被阿尔茨海默病的一个关键病理成分明显干扰。
A hallmark of Alzheimer's disease is accumulation of amyloid beta (A beta) deposits, which are associated with neuronal dysfunction, spine loss, and impaired Ca2+ homeostasis. Amyloid beta (A beta) 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 A beta, 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 A beta 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 A beta 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 A beta treatment. In contrast, Zn2+-dependent AKT phosphorylation is not mediated by mZnR/GPR39 and is not attenuated by A beta treatment. Thus, Zn2+ signaling via mZnR/GPR39 is distinctively disrupted by a critical pathological component of Alzheimer's disease.