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

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Title:	Urocortin modulates dopaminergic neuronal survival via inhibition of glycogen synthase kinase-3beta and histone deacetylase
Authors:	(Hsin-Yi Huang);林欣榮(Shinn-Zong Lin);(Wu-Fu Chen);(Kuo-Wei Lia);(Jon-Son Kuoe);(Mei-Jen Wang)*
Contributors:	醫學院免疫學研究所;中國附醫神經精神醫學中心;北港醫院神經外科
Keywords:	Urocortin;Corticotropin-releasing hormone;Neuropeptide;Dopaminergic neurons;Substantia nigra;cAMP;GSK-3β;HDAC
Date:	2010
Issue Date:	2010-09-27 15:43:11 (UTC+8)
Abstract:	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-3β (GSK-3β) 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-3β and HDAC contributes to UCN-mediated neuroprotection. These results suggest that dopaminergic neurons-derived UCN might be involved in an autocrine protective signaling mechanism.
Relation:	NEUROBIOLOGY OF AGING ():
Appears in Collections:	[Graduate Institute of Immunology] Journal articles

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