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.