Phosphorylation nitric-oxide synthases

Davis FI, Squire LR (1984) Protein synthesis and memory a review. Psychol Bull 96 518-559 Deisseroth K, Heist EK, Tsien RW (1998) Translocation of calmodulin to the nucleus supports CREB phosphorylation in hippocampal neurons. Nature 392 198-202 Dinerman J, Dawson TM, Schell MJ, Snowman A, Synder SH (1994) Endothelial nitric oxide synthase localized to hippocampal pyramidal cells implications for synaptic plasticity. Proc Natl Acad Sci U S A 91 4214-4218... 

Xu, J.W., Ikeda, K., and Yamori, Y., Cyanidin-3-glucoside regulates phosphorylation of endothelial nitric oxide synthase, FEES Lett., 574, 176, 2004. 

The synthesis of NO requires merely one step the conversion of L-arginine into NO and citrulline. This conversion is catalyzed by the nitric oxide synthase (NOS) enzyme. Three distinct isoforms of the NOS enzyme have been cloned Isoform I (nNOS chromosome 12) is a Ca -dependent neuronal form of the enzyme Isoform n (mNOS or iNOS chromosome 17) is a Ca +-independent macrophage inducible form of the enzyme found in microglia Isoform III (eNOS, chromosome 7) is a Ca +-dependent form found in the endothelial cells that line blood vessels. Since NO is an extremely important messenger substance, the NOS enzyme is exquisitely regulated by processes such as phosphorylation and hormonal control. 

Bredt, D. S., Ferris, C. D., and Snyder, S. H. (1992). Nitric oxide synthase regulatory sites. Phosphorylation by cyclic AMP-dependent protein kinase, protein kinase C, and calcium/calmodulin protein kinase identification of flavin and calmodulin binding sites. . Biol. Chem. 267, 10976-10981. 

Cai H, Li Z, Davis ME, Kanner W, Harrison DG, Dudley SC. Jr 2003. Akt dependent phosphorylation of serine 1179 and mitogen-activated protein kinase kinase/extra-cellular signal-regulated kinase 1/2 cooperatively mediate activation of the endothelial nitric-oxide synthase by hydrogen peroxide. Mol Pharmacol 63 325-331. 

Fleming I, Fisslthaler B, Dimmeler S, Kemp BE, Busse R. 2001. Phosphorylation of Thr(495) regulates Ca2 + /calmodulin-dependent endothelial nitric oxide synthase activity. Circ Res 88 E68-E75. 

Joy S, Siow RC, Rowlands DJ, Becker M, Wyatt AW, Aaronson PI, Coen CW, Kallo I, Jacob R, Mann GE. 2006. The isoflavone Equol mediates rapid vascular relaxation Ca2 + -independent activation of endothelial nitric-oxide synthase/Hsp90 involving ERK1/2 and Akt phosphorylation in human endothelial cells. J Biol Chem 281 27335-27345. 

Vecchione C, Maffei A, Colella S, Aretini A, Poulet R, Frati G, Gentile MT, Fratta L, Trimarco V, Trimarco B, Lembo G. Leptin effects on endothelial nitric oxide is mediated through Akt-endothelial nitric oxide synthase phosphorylation pathway. Diabetes. 2002 51 168-173. Diabetes. 2002 51 168-173. 

Dimmeler, S., Fleming, I., Fisslthaler, B., Hermann, C., Busse, R., andZeiher, A. M. 1999. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399 601-605. 

Dimmeler, S., Dernbach, E., and Zeiher, A. M. 2000. Phosphorylation of the endothelial nitric oxide synthase at ser-1177 is required for VEGF-induced endothelial cell migration. FEBS Lett. 477 258-262. 

A major signalling pathway involves activation of a protein kinase that phosphorylates inhibitor kB proteins (IkBs) that normally inhibit the function of the nuclear transcription factor NFkB. Phosphorylation of IkB by the serine/threonine-specific IkB kinases (IKKs) leads to NFkB de-inhibition, nuclear translocation and expression of pro-inflammatory proteins such as inducible cyclooxygenase (iCOX) (which generates prostaglandins), inducible nitric oxide synthase (iNOS) (which generates vasodilatory and toxic free radicalgenerating NO) and pro-inflammatory cytokines. 

Musicki B, Kramer ME, Becker RE, Burnett AL. Inactivation of phosphorylated endothelial nitric oxide synthase (Ser-1177) by 43. 0-GlcNAc in diabetes-associated erectile dysfunction. Proc. Natl. 

G. GarciaCardena, R. Fan, D. F. Stem, J. W. Liu and W. C. Sessa, Endothelial nitric-oxide synthase is regulated by tyrosine phosphorylation and interacts with caveolin-1. J Biol Chem 271, 27237-27240(1996). 

B. C. Berk, R. Aebersold and M. A. Corson, Identification of flow-dependent endothelial nitric-oxide synthase phosphorylation sites by mass spectrometry and regulation of phosphorylation and nitric oxide production by the phosphatidylinositol 3-kinase inhibitor LY294002. J Biol Chem 274, 30101-30108 (1999). 

C. Venema, Reciprocal phosphorylation and regulation of endothelial nitric-oxide synthase in response to bradykinin stimulation. J Biol Chem 276, 16587-16591 (2001). 

E. Butt, M. Bernhardt, A. Smolensk , P. Kotsonis, L. G. Frohlich, A. Sickmann, H. E. Meyer, S. M. Lohmann and H. H. Schmidt, Endothelial nitric-oxide synthase (type III) is activated and becomes calcium independent upon phosphorylation by cyclic nucleotide-dependent protein kinases. J Biol Chem 275, 5179-5187 (2000). 

V. J. Venema, M. B. Marrero and R. C. Venema, Bradykinin-stimulated tyrosine phosphorylation promotes endothelial nitric oxide synthase translocation to the cytoskeleton. Biochem Biophys Res Comm 226, 703-710(1996). 

Dawson TM, Steiner JP, Dawson VL, Dinerman JL, Uhl GR, Snyder SFI. Immunosuppressant FK506 enhances phosphorylation of nitric oxide synthase and protects against glutamate neurotoxicity. Proc Natl Acad Sci U S A 1993 90 9808-9812. 

Important cardioprotective targets are now recognized to be regulated by the insulin induced intracellular signaling. In fact, insulin induces phosphorylation and inactivation of the proapoptotic protein Bad and activation of the endothelial nitric oxide synthase... 

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