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- W885245866 abstract "The kidney potassium channel, ROMK (KCNJ1), controls urinary potassium excretion, in states of dietary potassium deficiency the channel is down-regulated by the endocytic clathrin adaptor protein, ARH. Inappropriate ROMK endocytosis contributes to hyperkalemia in Familial Hyperkalemic Hypertension (FHHt), a rare disorder caused by mutations in WNK 1, CUL3, and KLHL3. Here we explore how WNK1 and the E3 ligase complex containing CUL3 / KLHL3 regulate ARH ubiquitination, abundance, and ROMK expression. We found ARH directly binds to and is ubiquitinated by the CUL3/ KLHL3 E3 ligase complex, leading to ARH degradation. WNK1 blocks ARH degradation and KLHL3 binding by controlling phosphorylation of ARH at serine 14. Phosphorylation of ARH led to increased abundance as did the S14D phosphomimetic by blocking the direct ARH-KLHL3 interaction. Further we found WNK1 activates a kinase cascade resulting in the direct phosphoryation of ARH S-14 by the ERK5 kinase, as demonstrated by in vitro phosphorylation assays with recombinant ERK5 and in cells with the ERK5 inhibitor BIX02189, a finding consistent with the observed increase in activated ERK5 and ARH in mice fed a low K+ diet. These studies provide a molecular insight to understand how mutations in WNK1 and CUL3-KLHL3 acerbate channel endocytosis and disrupt potassium homeostasis in FHHt." @default.
- W885245866 created "2016-06-24" @default.
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- W885245866 date "2015-04-01" @default.
- W885245866 modified "2023-09-27" @default.
- W885245866 title "Familial Hyperkalemic Hypertension (FHHt) Proteins Form an Endocytic Switch for the Renal Excretory Channel, KCNJ1" @default.
- W885245866 doi "https://doi.org/10.1096/fasebj.29.1_supplement.666.9" @default.
- W885245866 hasPublicationYear "2015" @default.
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