CaMKII is involved in cadmium activation of MAPK and mTOR pathways leading to neuronal cell death

Abstract

Cadmium (Cd), a toxic environmental contaminant, induces neurodegenerative diseases. Recently we have shown that Cd elevates intracellular free calcium ion ([Ca2+]i) level, leading to neuronal apoptosis partly by activating mitogen-activated protein kinases (MAPK) and mammalian target of rapamycin (mTOR) pathways. However, the underlying mechanism remains to be elucidated. Here we show that the effects of Cd elevated [Ca2+]i on MAPK and mTOR network as well as neuronal cell death are through stimulating phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII). This is supported by the findings that chelating intracellular Ca2+ with BAPTA/AM or preventing Cd-induced [Ca2+]i elevation using 2-aminoethoxydiphenyl borate (2-APB) blocked Cd activation of CaMKII. Inhibiting CaMKII with KN93 or silencing CaMKII attenuated Cd activation of MAPK/mTOR pathways and cell death. Furthermore, inhibitors of mTOR (rapamycin), JNK (SP600125) and Erk1/2 (U0126), but not of p38 (PD169316), prevented Cd-induced neuronal cell death in part through inhibition of [Ca2+]i elevation and CaMKII phosphorylation. The results indicate that Cd activates MAPK/mTOR network triggering neuronal cell death, by stimulating CaMKII. Our findings underscore a central role of CaMKII in the neurotoxicology of Cd, and suggest that manipulation of intracellular Ca2+ level or CaMKII activity may be exploited for prevention of Cd-induced neurodegenerative disorders.

Convergent Ca 2+ and Zn 2+ signaling regulates apoptotic Kv2.1 K + currents

“…CaMKII has been implicated in neuronal cell death processes, because inhibition of this kinase is neuroprotective in both in vitro and in vivo injury models (61)(62)(63)(64). Nonetheless, as is the case for many other signaling kinase systems, CaMKII is associated with the regulation of both neuroprotective and neurodestructive cellular signaling pathways (65,66).…”

Calcium Homeostasis Disruption - a Bridge Connecting Cadmium-Induced Apoptosis, Autophagy and Tumorigenesis

“…In neuronal (PC12 and SH-SY5Y) cells, cadmium-induced intracellular Ca 2+ elevation, leading to cell apoptosis, is due to activation of the MAPK and mTOR signaling pathways through stimulation of phosphorylation of JNK, Erk1/2, p38 MAPK, mTOR and calcium/calmodulin (CaM)-dependent protein kinase II (CaMKII) [16,[21][22][23]. The elevation of intracellular Ca 2+ could activate CaM.…”

“…The elevation of intracellular Ca 2+ could activate CaM. CaM-mediated activation of MAPK and mTOR pathway plays an important role in Ca 2+ homeostasismediated apoptosis induced by cadmium [16,23].…”

“…Elevated intracellular Ca 2+ due to a low level cadmium can cause activation of the small guanine nucleotide-binding protein Ras [58], a protein which is related to some human cancers. Cadmium-elevated Ca 2+ can stimulate phosphorylation of CaMKII [23]. CaMKII is a multi-functional serine/threonine protein kinase, and has been shown to be involved in processes that cause tumor progression, including cell cycle regulation, apoptosis, differentiation, and cancer cell metastasis [59].…”

The Transient Receptor Potential Channel, Vanilloid 5, Induces Chondrocyte Apoptosis via Ca2+ CaMKII–Dependent MAPK and Akt/ mTOR Pathways in a Rat Osteoarthritis Model

“…CaMKII is activated in the presence of Ca 2+ and CaM, which leads to autophosphorylation, generating a Ca 2+ /CaM-independent form of the enzyme [8]. Increasing evidence indicates an elevation in cytoplasmic Ca 2+ levels activates the mitogen-activated protein kinase (MAPK) cascade.…”