Abstract
A peptide hormone, ghrelin, recognized for its role in the regulation of nitric oxide production has emerged as an important modulator of oral mucosal inflammatory responses to periodontopathic bacterium, P. gingivalis. As cSrc kinase plays a major role in controlling the activity of nitric oxide synthase (NOS) system, in this study we investigated the influence of P. gingivalis LPS on the processes of Src activation in rat sublingual gland acinar cells. The LPS-induced enhancement in the activity of inducible (i) iNOS and the impairment in constitutive (c) cNOS were reflected in the suppression in cSrc activity and the extent of its phosphorylation at Tyr416. Further, we show that the countering effect of ghrelin on the LPS-induced changes in cSrc activity and the extent of its phosphorylation was accompanied by a marked reduction in iNOS and the increase in cNOS activation through phosphorylation at Ser1179. Moreover, the effect of ghrelin on cSrc activation was associated with the kinase S-nitrosylation that was susceptible to the blockage by cNOS inhibition. Our findings suggest that P. gingivalis-induced up-regulation in iNOS leads to disturbances in cNOS phosphorylation that exerts the detrimental effect on the processes of cSrc activation through cNOS mediated S-nitrosylation. We also show that the effect of ghrelin on P. gingivalis-induced inflammatory changes are manifested in the enhancement in cSrc activation through S-nitrosylation and the increase in its phosphorylation at Tyr416.
Highlights
Ghrelin, a 28-amino acid peptide hormone, initially isolated from the stomach [1,2], and more recently identified in oral mucosa, saliva and the acinar cells of salivary glands [3], is recognized as an important modulator of oral mucosal inflammatory responses to periodontopathic bacterium, P. gingivalis through the regulation of nitric oxide synthase (NOS) isozyme system [4,5,6]
As cellular Src (cSrc) kinase plays a major role in controlling the activity of nitric oxide synthase (NOS) system, in this study we investigated the influence of P. gingivalis LPS on the processes of Src activation in rat sublingual gland acinar cells
As oral mucosal inflammatory responses to periodontopathic bacterium, P. gingivalis, are characterized by the disturbances in NO production, and since cSrc kinase plays a central role in transduction of signals that regulate the activity of NOS isozyme system [4,5,13,14], in this study we investigated the impact of P. gingivalis key virulence factor, LPS, on the cSrc kinase activity in sublingual salivary gland acinar cells
Summary
A 28-amino acid peptide hormone, initially isolated from the stomach [1,2], and more recently identified in oral mucosa, saliva and the acinar cells of salivary glands [3], is recognized as an important modulator of oral mucosal inflammatory responses to periodontopathic bacterium, P. gingivalis through the regulation of nitric oxide synthase (NOS) isozyme system [4,5,6]. The signaling mechanism that underlies the regulation of NO by ghrelin involves the stimulation of growth-hormone secretagogue receptor type 1a (GHSR1a), a seven-transmembrane G-protein coupled receptor, that leads to activation of heterotrimeric G protein-dependent network of protein kinases, including that of cellular Src (cSrc), a member of the non-receptor protein tyrosine kinase Src family [7,8,9,10]. The activity of cSrc is tightly regulated by reversible phosphorylation on Tyr527 and Tyr416 amino acid residues, which either inactivates or activates the kinase. The inhibitory phosphorylation at Tyr527 of C-terminal tail locks the kinase in an inactive dormant conformation through the interaction with its SH2 domain [9]. The dormant form of the enzyme is destabilized by dephosphorylation or displacement of the inhibitory Tyr527 from the SH2 binding pocket, ex-
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