title: Role of CDK5 in neuroprotection from serum deprivation by mu-opioid receptor agonist.
abstract: Cyclin-dependent kinase 5 (CDK5), a unique member of the CDK family of cyclin-dependent kinases, is predominantly expressed in postmitotic neurons with proposed roles in both cell survival and programmed cell death. To understand how CDK5 participates in such disparate cellular outcomes, we investigated whether activation of CDK5 could mediate neuroprotection from serum deprivation by mu-opioid receptor agonist in differentiated SH-SY5Y cells and primary hippocampal neurons. We found that CDK5 kinase activity decreased following serum deprivation in differentiated SH-SY5Y cells coincident with increased cell loss and activation of caspases cascade activation, which was reversed by opioid antagonist. Overexpression of CDK5 in serum-free medium reversed activation of caspase cascade and augmented DAMGO neuroprotection. Blocking CDK5 activity by pharmacologic inhibitor, roscovitine or overexpression of dominant negative CDK5 augmented activation of cell death markers and diminished mu-opioid receptor agonist protection. Reduction in CDK5 activity corresponded to reduction in protein levels of CDK5 activator p35 during serum deprivation which was also reversed by mu-opioid receptor agonist. Phosphorylation of STAT3 at Serine 727 by CDK5 decreased during serum deprivation, and partly recovered by mu-opioid agonist. PI3K signaling pathway was not required for CDK5-mediated mu-opioid neuroprotection against serum deprivation. These findings indicate that neuroprotection by mu-opioid receptor agonist against serum deprivation is mediated by activation of CDK5 through up-regulation of p35 and phosphorylation of STAT3 by CDK5 may contribute to the neuroprotection.
authors.affiliation: Neuroscience Research Institute and Department of Neurobiology, Key Laboratory for Neuroscience, Peking University, 38 Xueyuan Rd., Beijing 100083, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Wei-Yan
authors.initials: WY
authors.lastname: Xie
authors.forename: Yi
authors.initials: Y
authors.lastname: He
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Yan-Rui
authors.initials: YR
authors.lastname: Yang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Dong-Min
authors.initials: DM
authors.lastname: Yin
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Jordan-Sciutto
authors.forename: Ji-Sheng
authors.initials: JS
authors.lastname: Han
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D015153:Blotting, Western / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology*; D004347:Drug Interactions; D004622:Embryo, Mammalian; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D016296:Mutagenesis / Q000502:physiology; D009270:Naloxone / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors; D044967:Serum / Q000378:metabolism*; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D014162:Transfection / Q000379:methods
chemical_list: D016895:Culture Media, Serum-Free; D018696:Neuroprotective Agents; D017450:Receptors, Opioid, mu; D013778:Tetrazolium Salts; D013844:Thiazoles; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; D051360:Cyclin-Dependent Kinase 5; C022616:thiazolyl blue