Abstract
Disturbances in constitutive nitric oxide synthase (cNOS) activation associated with H. pylori colonization of gastric mucosa are considered of major consequences in defining the extent of inflammatory involvement. As rapid changes in cNOS activation are linked to the enzyme phosphorylation at the specific Ser/Thr residues, we investigated the influence of H. pylori LPS and gastric hormone, ghrelin, on the processes of phosphorylation of these two critical sites in gastric mucosal cells. We show that the LPS-induced reduction in cNOS activity is reflected in the phosphorylation on Thr497, while the countering effect of ghrelin is associated with a rapid increase in cNOS phosphorylation on Ser1179. Further, we demonstrate that cNOS phosphorylation on Thr497 as well as Ser1179 displays dependence on PKCδ. However, while the LPS-induced suppression in cNOS activation shows reliance on the phosphorylation of PKCδ and PI3K on Ser, the effect of ghrelin is manifested by the increase in phosphorylation of PKCδ and PI3K on Tyr, as well as membrane translocation and phosphorylation of Akt on Ser493. Thus, our findings suggest that the LPS-induced suppression in cNOS activation is mediated by PKCδ-controlled phosphorylation of PI3K on Ser that interferes with the membrane recruitment of Akt and promotes cNOS phosphorylation on Thr497, and that ghrelin-elicited up-regulation in cNOS activation relies on the PKCδ-directed phosphorylation of PI3K on Tyr that stimulates the membrane localization of Akt and enhances cNOS phosphorylation on Ser1179.
Highlights
Lipopolysaccharide (LPS), an outer membrane component of H. pylori, is recognized as a potent endotoxin capable of eliciting a course of mucosal inflammatory events that characterize gastritis and duodenal ulcers [1]-[4]
Our findings suggest that the LPS-induced suppression in constitutive nitric oxide synthase (cNOS) activation is mediated by PKCδ-controlled phosphorylation of PI3K on Ser that interferes with the membrane recruitment of Akt and promotes cNOS phosphorylation on Thr497, and that ghrelin-elicited up-regulation in cNOS activation relies on the PKCδ-directed phosphorylation of PI3K on Tyr that stimulates the membrane localization of Akt and enhances cNOS phosphorylation on Ser1179
Changes in cNOS activation through phosphorylation are considered of major consequences in defining the extent of gastric mucosal inflammatory involvement in response to H. pylori colonization [6] [7]
Summary
Lipopolysaccharide (LPS), an outer membrane component of H. pylori, is recognized as a potent endotoxin capable of eliciting a course of mucosal inflammatory events that characterize gastritis and duodenal ulcers [1]-[4]. The literature evidence indicates that the activity of cNOS may be influenced by phosphorylation of the enzyme protein at several residues of Ser, Thr and Tyr, but most extensively characterized are the functional consequences of cNOS phosphorylation on Ser1179and Thr497 [17]-[19] These data clearly established that phosphorylation of cNOS at the critical Ser1179 with the involvement of PI3K-dependent protein kinase Akt is responsible for a rapid stimulus-promoted cNOS activation, whereas the phosphorylation of cNOS at Thr497 by PKC is associated with a decrease in the enzyme activity [18]-[20]. These two posttranslational modifications contribute directly to a rapid regulation of cNOS-derived NO release
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