NYMC Faculty Publications

Title

PGF2alpha Regulates the Basolateral K Channels in the Distal Convoluted Tubule

Document Type

Article

Publication Date

August 2017

Department

Pharmacology

Abstract

Our aim is to examine the role of PGF2alpha 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 PGF2alpha had a biphasic effect on the 40-pS K channel in the DCT-PGF2alpha stimulated at low concentrations (less than 500 nM), while at high concentrations (above 1 microM), it inhibited the 40-pS K channels. Moreover, neither 13,14-dihydro-15-keto-PGF2alpha (a metabolite of PGF2alpha) nor PGE2 was able to mimic the effect of PGF2alpha 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 microM PGF2alpha 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 PGF2alpha on the 40-pS K channel. Conversely, the stimulatory effect of PGF2alpha on the 40-pS K channel was absent in the DCT treated with DPI, a NADPH oxidase (NOX) inhibitor. Also, adding 100 microM H2O2 mimicked the stimulatory effect of PGF2alpha and increased the 40-pS K channel activity in DCT. Moreover, the stimulatory effect of 500 nM PGF2alpha and H2O2 was not additive, suggesting the role of superoxide-related species in mediating the stimulatory effect of PGF2alpha 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 PGF2alpha and H2O2 on the 40-pS K channel. We conclude that PGF2alpha 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.

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