Protective effect of urocortin on 1-methyl-4-phenylpyridinium-induced dopaminergic neuronal death.
Recent studies have indicated that the corticotropin releasing hormone (CRF)-related peptide, urocortin, restores key indicators of damage in animal models for Parkinson's disease (PD). However, the molecular mechanism for the neuroprotective effect of urocortin is unknown. 1-Methy-4-phenylpyridinium (MPP(+)) induces dopaminergic neuronal death. In the present study, MPP(+)-induced neuroblastoma SH-SY5Y cell death was significantly attenuated by urocortin in a concentration-dependent manner. The protective effect of urocortin involved the activation of CRF receptor type 1, resulting in the increase of cyclic AMP (cAMP) levels. Various cAMP-enhancing reagents mimicked the effect of urocortin, while inhibitors for protein kinase A (PKA) blocked the effect of urocortin, strongly implicating the involvement of cAMP-PKA pathway in the neuroprotective effect of urocortin on MPP(+)-induced cell death. As the downstream of this signal pathway, urocortin promoted phosphorylation of both glycogen synthase kinase 3β and extracellular signal-regulated kinases, which are known to promote cell survival. These neuroprotective signaling pathways of urocortin may serve as potential therapeutic targets for PD.
Kim
Yonjung
Y
Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 440-746, Korea.
Park
Myoung Kyu
MK
Chung
Sungkwon
S
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054832:Urocortins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000099052:CRF Receptor, Type 1
D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; D000099052:CRF Receptor, Type 1; D000242:Cyclic AMP; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine