Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 110, Issue 1, Pages 112-117Publisher
WILEY
DOI: 10.1002/jcb.22515
Keywords
Cdk5; eNOS; NO; ALZHEIMER'S DISEASES; PARKINSON'S DISEASES
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Funding
- National Cheng Kung University Hospital [NCKUH-9701004]
- National Science Council [NSC 97-2311-B-006-003-MY3, NSC-98-3112-B-006-012]
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Phosphorylation of endothelial nitric oxide synthase (eNOS) is key mechanism in response to various forms of cellular stimulation. Through protein nitration by peroxynitrite, eNOS is believed to be responsible for the major abnormalities in several important neurodegenerative diseases including Alzheimer's (AD) and Parkinson's diseases (PD). Recent studies provide important in vivo evidence that hyperactivation of Cdk5 by p25 plays an essential role in the cell death of neurons in experimental models of AD and PD. This study focuses on the functional regulation of eNOS by Cdk5/p35 complex in a phosphorylation dependent manner. Our results showed that Cdk5 can phosphorylate eNOS both in vitro and in vivo. In vitro kinase assay together with the bioinformatic analysis and site direct mutagenesis revealed that Ser-113 is the major phosphorylation site for Cdk5. Most interestingly, the nitrite production was significantly reduced in eNOS and Cdk5/p35 co-transfected SH-SY5Y cells when compared with co-transfection of Cdk5/p35 and S113A. Together, our data suggest that Cdk5 can phosphorylate eNOS at the Ser-113 site and down-regulate eNOS-derived NO levels. J. Cell. Biochem. 110: 112-117,2010. (C) 2010 Wiley-Liss, Inc.
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