p38 and ERK, but not JNK, 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 μM) 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.