RT Journal Article SR Electronic T1 Zn2+ Induces Stimulation of the c-Jun N-Terminal Kinase Signaling Pathway through Phosphoinositide 3-Kinase JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 981 OP 986 DO 10.1124/mol.59.5.981 VO 59 IS 5 A1 Soo-Jung Eom A1 Eun Young Kim A1 Ji Eun Lee A1 Hyo Jung Kang A1 Jaekyung Shim A1 Seong Up Kim A1 Byoung Joo Gwag A1 Eui-Ju Choi YR 2001 UL http://molpharm.aspetjournals.org/content/59/5/981.abstract AB Zn2+, one of the most abundant trace metal ions in mammalian cells, modulates the functions of many regulatory proteins associated with a variety of cellular activities. In the central nervous system, Zn2+ is highly localized in the cerebral cortex and hippocampus. It has been proposed to play a role in normal brain function as well as in the pathophysiology of certain neurodegenerative disorders. We here report that Zn2+induced stimulation of the c-Jun N-terminal kinase (JNK) pathway in mouse primary cortical cells and in various cell lines. Exposure of cells to Zn2+ resulted in the stimulation of JNK and its upstream kinases including stress-activated protein kinase kinase and mitogen-activated protein kinase kinase kinase. Zn2+also induced stimulation of phosphoinositide 3-kinase (PI3K) The Zn2+-induced JNK stimulation was blocked by LY294002, a PI3K inhibitor, or by a dominant-negative mutant of PI3Kγ. Furthermore, overexpression of Rac1N17, a dominant negative mutant of Rac1, suppressed the Zn2+- and PI3Kγ-induced JNK stimulation. The stimulatory effect of Zn2+ on both PI3K and JNK was repressed by the free-radical scavenging agentN-acetylcysteine. Taken together, our data suggest that Zn2+ induces stimulation of the JNK signaling pathway through PI3K-Rac1 signals and that the free-radical generation may be an important step in the Zn2+ induction of the JNK stimulation.