Adverse effect of FTY720P on colonic Na<sup>+</sup>/K<sup>+</sup> ATPase is mediated via ERK, p38MAPK, PKC, and PI3K

Journal of Applied Toxicology - Tập 43 Số 2 - Trang 220-229 - 2023
Reem Rida1, Rawad Hodeify2, Sawsan Ibrahim Kreydiyyeh1
1Department of Biology, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon
2Department of Biotechnology, School of Arts and Sciences, American University of Ras Al Khaimah, Ras Al Khaimah, United Arab Emirates

Tóm tắt

AbstractFTY720P, an analogue of sphingosine 1‐phosphate, has emerged lately as a potential causative agent of inflammatory bowel disease, in which electrolytes movements driven by the sodium gradient established by the Na+/K+ ATPase are altered. We showed previously in Caco‐2 cells, a 50% FTY720P‐induced decrease in the ATPase activity, mediated via S1PR2 and PGE2. This work aims at delineating the mechanism underlying PGE2 release and at investigating if the ATPase inhibition is due to changes in its abundance. The activity of the ATPase and the localization of a GFP‐tagged Na+/K+‐ATPase α1‐subunit were assessed in cells treated with 7.5 nM FTY720P. The involvement of ERK, p38 MAPK, PKC, and PI3K was studied in cells treated with 7.5 nM FTY720P or 1 nM PGE2 in presence of their inhibitors, or by determining changes in the protein expression of their activated phosphorylated forms. Imaging data showed ∼30% reduction in the GFP‐tagged Na+/K+ ATPase at the plasma membrane. Both FTY720P and PGE2 showed, respectively, 50% and 60% reduction in ATPase activity that disappeared when p38 MAPK, PKC, and PI3K were inhibited individually but not with ERK inhibition. The effect of FTY720P was imitated by PMA, an activator of PKC. Western blotting revealed inhibition of ERK by FTY720P. It was concluded that FTY720P, through activation of S1PR2, downregulates the Na+/K+ ATPase by inhibiting ERK, which in turn activates p38 MAPK leading to the sequential activation of PKC and PI3K, PGE2 release, and a decrease in the Na+/K+ ATPase activity and membrane abundance.

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Journal of Applied Toxicology

Tập 43 Số 2

220-229

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