p38 and ERK, but not INK, are involved in copper-induced apoptosis in cultured cerebellar granule neurons

Copper (Cu2+) is an essential element for a variety of cellular functions; however, it is involved in neurotoxic events at excessive doses. Mechanisms of Cu2+-induced neurotoxicity are not well understood. Here, we studied the toxic effects of Cu2+ on cultured cerebellar granule neurons (cCGNs). Treatment of cCGNs with CuCl2 (50 and 75 mu M) caused a concentration- and time-dependent cell death with apoptotic characters, including chromatin condensation and DNA ladder. Cu2+ potently induced reactive oxygen species (ROS), and quickly and slightly increased the intracellular concentration of calcium. Western blot assay showed that Cu2+ 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 Cu2+ 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. (C) 2009 Elsevier Inc. All rights reserved.