RyRs mediate lead-induced neurodegenerative disorders through calcium signaling pathways

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

doi:10.1016/j.scitotenv.2019.134901

RyRs mediate lead-induced neurodegenerative disorders through calcium signaling pathways

Sci Total Environ. 2020 Jan 20:701:134901. doi: 10.1016/j.scitotenv.2019.134901. Epub 2019 Nov 1.

Authors

Fankun Zhou¹, Guihua Du¹, Jie Xie¹, Junwang Gu¹, Qiyue Jia¹, Ying Fan¹, Han Yu¹, Zhipeng Zha¹, Kai Wang¹, Lu Ouyang¹, Lijian Shao¹, Chang Feng¹, Guangqin Fan²

Affiliations

¹ Department of Occupational Health and Toxicology, School of Public Health, Nanchang University, Nanchang 330006, PR China; Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang 330006, PR China.
² Department of Occupational Health and Toxicology, School of Public Health, Nanchang University, Nanchang 330006, PR China; Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang 330006, PR China. Electronic address: fanguangqin@ncu.edu.cn.

PMID: 31710906
DOI: 10.1016/j.scitotenv.2019.134901

Abstract

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 and in 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.

Keywords: Calcium disorder; Calcium signaling pathway; Lead exposure; Neurodegeneration; Ryanodine receptors.

MeSH terms

Animals
Calcium Signaling / drug effects
Hippocampus / metabolism
Lead / toxicity*
Male
Neurodegenerative Diseases / chemically induced*
Rats
Ryanodine Receptor Calcium Release Channel / metabolism*

Substances

Ryanodine Receptor Calcium Release Channel
Lead