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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/F1299    most recent 00293.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Jin, Y. Articles by Wang, W.-H. Search for Related Content PubMed PubMed Citation Articles by Jin, Y. Articles by Wang, W.-H.

PGE₂ inhibits apical K channels in the CCD through activation of the MAPK pathway

¹Department of Pharmacology, Harbin Medical University, Harbin, China; and ²Department of Pharmacology, New York Medical College, Valhalla, New York

Submitted 26 June 2007 ; accepted in final form 26 July 2007

We used the patch-clamp technique and Western blot analysis to explore the effect of PGE₂ on ROMK-like small-conductance K (SK) channels and Ca²⁺-activated big-conductance K channels (BK) in the cortical collecting duct (CCD). Application of 10 µM PGE₂ inhibited SK and BK channels in the CCD. Moreover, either inhibition of PKC or blocking mitogen-activated protein kinase (MAPK), P38 and ERK, abolished the effect of PGE₂ on SK channels in the CCD. The effect of PGE₂ on SK channels was completely blocked in the presence of SC-51089, a specific EP1 receptor antagonist, and mimicked by application of sulprostone, an agonist for EP1 and EP3 receptors. To determine whether PGE₂ stimulates the phosphorylation of P38 and ERK, we treated mouse CCD cells (M-1) with PGE₂. Application of PGE₂ significantly stimulated the phosphorylation of P38 and ERK within 5 min. The dose-response curve of PGE₂ effect shows that 1, 5, and 10 µM PGE₂ increased the phosphorylation of P38 and ERK by 20–21, 50–80, and 80–100%, respectively. The stimulatory effect of PGE₂ on MAPK phosphorylation was not affected by indomethacin but abolished by inhibition of PKC. This suggests that the effect of PGE₂ on MAPK phosphorylation is PKC dependent. Also, the expression of cyclooxygenase II and PGE₂ concentration in renal cortex and outer medulla was significantly higher in rats fed a K-deficient diet than those on a normal-K diet. We conclude that PGE₂ inhibits SK and BK channels and that there is an effect of PGE₂ on SK channels in the CCD through activation of EP1 receptor and MAPK pathways. Also, high concentrations of PGE₂ induced by K restriction may be partially responsible for increasing MAPK activity during K restriction.

cyclooxygenase; arachidonic acid; P38; ERK; ROMK; renal K secretion