RyRs mediate lead-induced neurodegenerative disorders through calcium signaling pathways
RyRs mediate lead-induced neurodegenerative disorders through calcium signaling pathways
复制标题
RyRs 通过钙信号通路介导铅诱发的神经退行性疾病。
DOI：
10.1016/j.scitotenv.2019.134901
复制
发表时间：
2020
影响因子：
9.8
通讯作者：
Guangqin Fan
中科院分区：
文献类型：
--
作者：
Fankun Zhou;Guihua Du;Jie Xie;Junwang Gu;Qiyue Jia;Ying Fan;Han Yu;Zhipeng Zha;Kai Wang;Lu Ouyang;Lijian Shao;Chang Feng;Guangqin Fan
重金属铅（Pb）广泛存在于环境中，可引起神经退行性病变。越来越多的证据表明，兰尼碱受体（RyRs）在神经退行性变的大脑中起着重要作用。然而，异常的RyR水平是否有助于铅诱导的神经变性在很大程度上仍然未知。在本研究中，我们报告了RyRs水平升高在铅诱导的神经退行性变中的重要作用。结果表明，铅可上调大鼠海马组织和大鼠嗜铬细胞瘤（PC 12）细胞中RyRs的表达。此外，铅暴露还可引起大鼠神经退行性认知障碍，抑制脑片长时程增强（LTP），增加神经元内游离钙浓度（[Ca ~（2+）]i），抑制Ca ~（2+）/钙调蛋白依赖性蛋白激酶II（CaMK II）和环腺苷3′的磷酸化，5′-单磷酸（cAMP）反应元件结合蛋白（CREB）以及抗凋亡蛋白B细胞淋巴瘤2（Bcl 2）的表达，并在体内外激活细胞外调节蛋白激酶（Erk）蛋白的磷酸化。此外，敲低RyR 3可显著降低铅暴露后PC 12细胞内[Ca 2 +]i水平，增加CaMKIIα和CREB磷酸化水平，降低Erk磷酸化水平，延长铅暴露后与认知功能相关的神经突起生长。此外，用RyRs激动剂治疗显示RyRs参与Pb诱导的大鼠脑切片LTP抑郁。总之，我们确定Pb介导的RyR上调通过高水平的游离钙、钙依赖性CaMKIIα/CREB记忆信号通路的抑制和钙依赖性Erk/Bcl 2凋亡信号通路的激活导致神经退行性变。这些关于铅对RyR水平影响的研究结果可以进一步提高我们对铅诱导的神经毒性的理解，并为拮抗铅诱导的神经退行性疾病提供有前途的分子靶点。
Heavy metal lead (Pb) is widely distributed in the environment and can induce neurodegeneration. Accumulating evidence has shown that ryanodine receptors (RyRs) play vital roles in neurodegenerative brain. However, whether aberrant RyRs levels contribute to Pb-induced neurodegeneration has largely remained unknown. In the present study, we report the important role of elevated levels of RyRs in Pb-induced neurodegeneration. Pb was found to upregulate the levels of RyRs in the rat hippocampal tissues and rat pheochromocytoma (PC12) cells. Furthermore, exposure to Pb induced neurodegenerative cognitive impairment in rats, depressed the long-term potentiation (LTP) in the rat brain slices, increased the neuronal intracellular free calcium concentration ([Ca2+]i), inhibited the phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and cyclic adenosine 3′,5′-monophosphate (cAMP) response element binding protein (CREB) as well as the expression of anti-apoptotic protein B-cell lymphoma 2 (Bcl2), and activated the phosphorylation of extracellular regulated protein kinases (Erk) protein both in vitro andin vivo. In addition, the knockdown of RyR3 in PC12 cells significantly decreased the [Ca2+]i levels, increased the CaMKIIα and CREB phosphorylation, decrease the phosphorylation of Erk, and elongated the cognitive function-related neurite outgrowth after exposure to Pb. Moreover, treatment with a RyRs agonist showed the involvement of RyRs in Pb-induced depression in LTP in the rat brain slices. In summary, we determined that Pb-mediated upregulation of RyRs led to neurodegeneration via high levels of free calcium, depression of the calcium-dependent CaMKIIα/CREB mnemonic signaling pathway, and activation of the calcium-dependent Erk/Bcl2 apoptotic signaling pathway. These findings on the impact of Pb on the levels of RyRs could further improve our understanding of Pb-induced neurotoxicity and provide a promising molecular target to antagonize Pb-induced neurodegenerative diseases.