4.5 Article

Urocortin modulates dopaminergic neuronal survival via inhibition of glycogen synthase kinase-3β and histone deacetylase

期刊

NEUROBIOLOGY OF AGING
卷 32, 期 9, 页码 1662-1677

出版社

ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2009.09.010

关键词

Urocortin; Corticotropin-releasing hormone; Neuropeptide; Dopaminergic neurons; Substantia nigra; cAMP; GSK-3 beta; HDAC

资金

  1. Tzu Chi General Hospital [TCRD96-22, TCRD97-20]
  2. National Science Council, Taiwan [NSC 95-2314-B-303-015]

向作者/读者索取更多资源

Urocortin (UCN) is a member of the corticotropin-releasing hormone (CRH) family of neuropeptides that regulates stress responses. Although UCN is principally expressed in dopaminergic neurons in rat substantia nigra (SN), the function of UCN in modulating dopaminergic neuronal survival remains unclear. Using primary mesencephalic cultures, we demonstrated that dopaminergic neurons underwent spontaneous cell death when their age increased in culture. Treatment of mesencephalic cultures with UCN markedly prolonged the survival of dopaminergic neurons, whereas neutralization of UCN with anti-UCN antibody accelerated dopaminergic neurons degeneration. UCN increased intracellular cAMP levels followed by phosphorylating glycogen synthase kinase-3 beta (GSK-3 beta) on Ser9. Moreover, UCN directly inhibited the histone deacetylase (HDAC) activity and induced a robust increase in histone H3 acetylation levels. Using pharmacological approaches, we further demonstrated that inhibition of GSK-3 beta and HDACcontributes to UCN-mediated neuroprotection. These results suggest that dopaminergic neurons-derived UCN might be involved in an autocrine protective signaling mechanism. (C) 2009 Elsevier Inc. All rights reserved.

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