p38 Activation Is Required Upstream of Potassium Current Enhancement and Caspase Cleavage in Thiol Oxidant-Induced Neuronal Apoptosis

摘要: Oxidant-induced neuronal apoptosis has been shown to involve potassium and zinc dysregulation, energetic dysfunction, activation of stress-related kinases, caspase cleavage. The temporal ordering interdependence these events was investigated in primary cultures exposed the sulfhydryl oxidizing agent 2,2′-dithiodipyridine (DTDP), a compound that induces intracellular release zinc. We previously observed tetraethylammonium (TEA), high extracellular potassium, or cysteine protease inhibitors block induced by DTDP. now report both p38 signal-regulated kinase phosphorylation are evident within 2 hr brief exposure 100 μm However, only inhibition is capable blocking oxidant-induced toxicity. Cyclohexamide actinomycin D does not attenuate DTDP-induced cell death, suggesting posttranslational modification existing targets, rather than transcriptional activation, responsible for deleterious effects p38. Indeed, an early robust increase TEA-sensitive channel currents DTDP attenuated but inhibition. Moreover, we found required 3 9 cleavage, enhancement activation. Finally, toxicity could be blocked with niacinamide benzamide, poly (ADP-ribose) synthetase. Based on findings, conclude oxidation groups targets results release, phosphorylation, currents, translationally independent apoptotic death.