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.
College of Pharmacy and Research Center for Bioresource and Health, Chungbuk National University, 52, Naesudong-ro, Heungduk-gu, Cheongju 361-763, Republic of Korea.
Hyun Jin
HJ
Park
Keun Hong
KH
Park
Keon Sung
KS
Shin
Myung Koo
MK
Lee
D000818:Animals; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity*; D016716:PC12 Cells; D010300:Parkinson Disease; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D051025:bcl-Associated Death Protein / Q000378:metabolism*
C494821:Bad protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein; D016627:Oxidopamine; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053148:Caspase 3; D002118:Calcium
6-Hydroxydopamine; Bad; Cyclic AMP; Extracellular signal-regulated kinase (ERK); PC12 cells