Submitted on June 26, 2007
Accepted on July 26, 2007
PGE2 inhibits apical K channels in the CCD through activation of the MAPK pathway
Yan Jin1, ZhiJian Wang1, Yan Zhang1, Baofeng Yang2, and WenHui Wang3*
1 Pharmacology, New York Medical College, Valhalla, New York, United States
2 Pharmacology, Harbin Medical University, Harbin, China
3 Dept of Pharmacology, New York Medical College, Valhalla, New York, United States
* To whom correspondence should be addressed. E-mail: wenhui_wang{at}nymc.edu.
We used the patch clamp technique and Western blot 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. The effect of PGE2 on SK channels was 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 with PGE2 . Application of PGE2 significantly stimulated the phosphorylation of P38 and ERK within 5 min. 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 (COXII) and PGE2 concentration in renal cortex and outer medulla were significantly higher in rats fed on K-deficient (KD) diet than those on a normal K (NK). We conclude that PGE2 inhibits SK and BK channels and that the 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.
