title: PGF2αregulates the basolateral K channels in the distal convoluted tubule.
abstract: Our aim is to examine the role of PGF2αreceptor (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 PGF2αhad a biphasic effect on the 40-pS K channel in the DCT-PGF2αstimulated 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 PGE2was able to mimic the effect of PGF2αon 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 PGF2αon the K channel. Moreover, stimulation of PKC inhibited the 40-pS K channel in the DCT, suggesting that PKC mediates the inhibitory effect of PGF2αon the 40-pS K channel. Conversely, the stimulatory effect of PGF2αon the 40-pS K channel was absent in the DCT treated with DPI, a NADPH oxidase (NOX) inhibitor. Also, adding 100 µM H2O2mimicked the stimulatory effect of PGF2αand increased the 40-pS K channel activity in DCT. Moreover, the stimulatory effect of 500 nM PGF2αand H2O2was not additive, suggesting the role of superoxide-related species in mediating the stimulatory effect of PGF2αon 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 PGF2αand H2O2on the 40-pS K channel. We conclude that PGF2αat 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.
authors.affiliation: Department of Physiology, Harbin Medical University, Harbin, China; and.|Department of Pharmacology, New York Medical College, Valhalla, New York.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York.
authors.forename: Chengbiao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York.
authors.forename: Xiao-Tong
authors.initials: XT
authors.lastname: Su
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York.
authors.forename: Dao-Hong
authors.initials: DH
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York.
authors.forename: Peng
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York.
authors.forename: Michal L
authors.initials: ML
authors.lastname: Schwartzman
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York wenhui_wang@nymc.edu.
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Wang
mesh_terms: D000818:Animals; D015237:Dinoprost / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D007686:Kidney Tubules, Distal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D015221:Potassium Channels; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor; D015237:Dinoprost; D019255:NADPH Oxidases; D019061:src-Family Kinases; D011493:Protein Kinase C
keywords: Kcnj10; Kcnj16; NCC; PKC; cyclooxygenase