p38 and ERK, but not JNK, are involved in copper-induced apoptosis in cultured cerebellar granule neurons.
Copper (Cu(2+)) is an essential element for a variety of cellular functions; however, it is involved in neurotoxic events at excessive doses. Mechanisms of Cu(2+)-induced neurotoxicity are not well understood. Here, we studied the toxic effects of Cu(2+) on cultured cerebellar granule neurons (cCGNs). Treatment of cCGNs with CuCl(2) (50 and 75muM) caused a concentration- and time-dependent cell death with apoptotic characters, including chromatin condensation and DNA ladder. Cu(2+) potently induced reactive oxygen species (ROS), and quickly and slightly increased the intracellular concentration of calcium. Western blot assay showed that Cu(2+) increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and ERK1/2, but not that of JNK-1. Pharmacological inhibition of calcium influx, p38 MAPK and ERK1/2 attenuated the Cu(2+) toxicity in cCGNs. These findings demonstrate that p38 MAPK and ERK1/2, but not JNK, are involved in apoptosis of cCGNs induced by copper, and p38 and ERK may be the downstream effectors of ROS and calcium signaling.
Chen
Xiaohong
X
Department of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Lan
Xiujian
X
Mo
Suilin
S
Qin
Jian
J
Li
Wenming
W
Liu
Peiqing
P
Han
Yifan
Y
Pi
Rongbiao
R
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D003300:Copper / Q000633:toxicity*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D017382:Reactive Oxygen Species; D003300:Copper; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium