Gene/Protein
Disease
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Enzyme
Compound
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Gene/Protein
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Target Concepts:
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Query: EC:2.7.11.17 (
CaMKII
)
4,029
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
It has recently been demonstrated that exogenous addition of low concentrations (< 15 microM) of lysophosphatidyl choline (LPC,
palmitic acid
in the sn-1 position) induces a transient increase in taurine efflux from HeLa cells in a process that seems to involve generation of reactive oxygen species (ROS) and tyrosine phosphorylation (J. Membrane Biol. 176 (2000) 175-185). We now demonstrate that LPC also induces release of taurine under isotonic conditions in mouse fibroblast (NIH/3T3) and Ehrlich ascites tumor cells. Furthermore, we show that in the case of HeLa cells addition of the calmodulin antagonist W-7 (50 microM) or the
calmodulin-dependent kinase II
(
CaMKII
) inhibitor KN-62 (10 microM) reduces the LPC-induced taurine release under isotonic conditions. Conversely, addition of a standard protein kinase C (PKC) inhibitor chelerythrine (10 microM) leads to a potentiation of the LPC-induced taurine efflux, whereas direct activation of PKC by the phorbol ester PMA has no effect. It is suggested that the putative generation of ROS following addition of LPC is modulated by calmodulin/
CaMKII
, and that the effect of chelerythrine is more likely related to the ROS production than to PKC inhibition.
...
PMID:Lysophosphatidylcholine-induced taurine release in HeLa cells involves protein kinase activity. 1191 68
Transient Receptor Potential Melastatin-2 (TRPM2) is a nonselective cation channel mediating Ca
2+
influx in response to oxidative stress. Given that insulin resistance-related endothelial dysfunction in obesity attributes to fatty-acid-induced reactive oxygen species (ROS) overproduction, in this study, we addressed the possible role of TRPM2 in obesity-related endothelial insulin resistance and the underlying mechanisms. Whole-cell patch clamp technique, intracellular Ca
2+
concentration measurement, western blot, vasorelaxation assay, and high-fat diet (HFD)-induced obese model were employed to assess the relationship between TRPM2 and endothelial insulin response. We found that both the expression and activity of TRPM2 were higher in endothelial cells of obese mice.
Palmitate
rose a cationic current in endothelial cells which was inhibited or enlarged by TRPM2 knockdown or overexpression. Silencing of TRPM2 remarkably improved insulin-induced endothelial Akt activation, nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production, while TRPM2 overexpression resulted in the opposite effects. Furthermore, TRPM2-mediated Ca
2+
entry,
CaMKII
activation and the following activation of PERK/ATF4/TRB3 cascade were involved in the mechanism of obesity or palmitate-induced endothelial insulin resistance. Notably, in vivo study, knockdown of TRPM2 with adeno-associated virus harboring short-hairpin RNA (shRNA) against TRPM2 alleviated endothelial insulin resistance and ameliorated endothelium-dependent vasodilatation in obese mice. Thus, these results suggest that TRPM2-activated Ca
2+
signaling is necessary to induce insulin resistance-related endothelial dysfunction in obesity. Downregulation or pharmacological inhibition of TRPM2 channels may lead to the development of effective drugs for treatment of endothelial dysfunction associated with oxidative stress state.
...
PMID:Free fatty acid-induced H
2
O
2
activates TRPM2 to aggravate endothelial insulin resistance via Ca
2+
-dependent PERK/ATF4/TRB3 cascade in obese mice. 3144 5
