The roles of cyclic AMP-ERK-Bad signaling pathways on 6-hydroxydopamine-induced cell survival and death in PC12 cells.

The roles of cyclic AMP (cAMP)-ERK1/2-Bad signaling pathways in 6-hydroxydopamine (6-OHDA)-induced cell survival and death were investigated. In PC12 cells, 6-OHDA (10-100μM) concentration-dependently increased the intracellular levels of cAMP mediated by the Ca(2+)-CaMKII-adenylyl cyclase system. 6-OHDA at the non-toxic level (10μM) induced transient ERK1/2 phosphorylation and BadSer112 phosphorylation, which maintained cell survival. In contrast, the high levels of cAMP induced by toxic levels (50 and 100μM) of 6-OHDA induced sustained ERK1/2 phosphorylaton and BadSer155 phosphorylation. The cells then moved to cell death process through Bcl2 phosphorylation and caspase-3 activation. BadSer155 phosphorylation by 6-OHDA was inhibited by PKA (H89) and MEK (U0126) inhibitors, indicating that it was mediated via the cAMP-PKA-sustained ERK1/2 system. In SK-N-BE(2)C cells, the non-toxic level of 6-OHDA also showed transient ERK1/2 phosphorylation and BadSer112 phosphorylation, and toxic levels of 6-OHDA exhibited sustained ERK1/2 phosphorylation and BadSer155 phosphorylation. These results suggest that ERK1/2 phosphorylation by 6-OHDA shows biphasic functions on cell survival and death in PC12 cells. It is, therefore, proposed that the cAMP-ERK1/2-Bad signaling pathways incurred by toxic levels of 6-OHDA play a role in dopamine neuron death of animal models of Parkinson's disease.