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Abstract：
Our aim is to examine the role of PGF2α receptor (FP), a highly expressed prostaglandin receptor in the distal convoluted tubule (DCT) in regulating the basolateral 40-pS K channel. The single-channel studies demonstrated that PGF2α had a biphasic effect on the 40-pS K channel in the DCT-PGF2α stimulated at low concentrations (less than 500 nM), while at high concentrations (above 1 µM), it inhibited the 40-pS K channels. Moreover, neither 13,14-dihydro-15-keto-PGF2α (a metabolite of PGF2α) nor PGE2 was able to mimic the effect of PGF2α on the 40-pS K channel in the DCT. The inhibition of PKC had no significant effect on the 40-pS K channel; however, it abrogated the inhibitory effect of 5 µM PGF2α on the K channel. Moreover, stimulation of PKC inhibited the 40-pS K channel in the DCT, suggesting that PKC mediates the inhibitory effect of PGF2α on the 40-pS K channel. Conversely, the stimulatory effect of PGF2α on the 40-pS K channel was absent in the DCT treated with DPI, a NADPH oxidase (NOX) inhibitor. Also, adding 100 µM H2O2 mimicked the stimulatory effect of PGF2α and increased the 40-pS K channel activity in DCT. Moreover, the stimulatory effect of 500 nM PGF2α and H2O2 was not additive, suggesting the role of superoxide-related species in mediating the stimulatory effect of PGF2α on the 40-pS K channel. The inhibition of Src family tyrosine protein kinase (SFK) not only inhibited the 40-pS K channel in the DCT but also completely abolished the stimulatory effects of PGF2α and H2O2 on the 40-pS K channel. We conclude that PGF2α at low doses stimulates the basolateral 40-pS K channel by a NOX- and SFK-dependent mechanism, while at high concentrations, it inhibits the K channel by a PKC-dependent pathway.
摘要：
我们的目的是研究PGF2α受体(FP)的作用，远端曲小管（DCT）中高表达的前列腺素受体，可调节基底外侧40-pSK通道。单通道研究表明，PGF2α对低浓度（小于500nM）刺激的DCT-PGF2α中的40-pSK通道具有双相作用，在高浓度（高于1µM）时，它抑制了40-pSK通道。此外，13,14-二氢-15-酮-PGF2α（PGF2α的代谢物）和PGE2都无法模仿PGF2α对DCT中40-pSK通道的影响。PKC的抑制对40-pSK通道没有显着影响；但是，它消除了5µMPGF2α对K通道的抑制作用。此外，刺激PKC抑制了DCT中的40-pSK通道，提示PKC介导PGF2α对40-pSK通道的抑制作用。相反，在DPI处理的DCT中，PGF2α对40-pSK通道的刺激作用不存在，NADPH氧化酶(NOX)抑制剂。此外，添加100µMH2O2模拟了PGF2α的刺激作用，并增加了DCT中的40-pSK通道活性。此外，500nMPGF2α和H2O2的刺激作用不是累加的，提示超氧化物相关物种在介导PGF2α对40-pSK通道的刺激作用中的作用。抑制Src家族酪氨酸蛋白激酶（SFK）不仅抑制了DCT中的40-pSK通道，而且完全消除了PGF2α和H2O2对40-pSK通道的刺激作用。我们得出结论，低剂量的PGF2α通过NOX和SFK依赖性机制刺激基底外侧40-pSK通道，在高浓度下，它通过PKC依赖性途径抑制K通道。
