title: WNK1 kinase isoform switch regulates renal potassium excretion.
abstract: Members of the WNK family of serine/threonine kinases have been implicated as important modulators of salt homeostasis, regulating the balance between renal sodium reabsorption and potassium excretion. Gain-of-expression mutations in the WNK1 gene uncouple Na(+) and K(+) balance and cause a familial disorder of diminished renal potassium excretion, excessive sodium retention, and hypertension (pseudohypoaldosteronism type II or Gordon's syndrome). Alternative splicing of the WNK1 gene produces a kidney-specific short form of WNK1 (KS-WNK1) and a more ubiquitous long form (L-WNK1), but it is not clear how either of these isoforms influence renal potassium excretion. Here we demonstrate that KS-WNK1 and L-WNK1 converge in a pathway to regulate the renal outer-medullary K(+) channel, Kir1.1. Reconstitution studies in Xenopus oocytes reveal that L-WNK1 significantly inhibits Kir1.1 by reducing cell surface localization of the channel. A catalytically inactive L-WNK1 mutant has no inhibitory effect on Kir1.1, indicating that channel inhibition depends on kinase activity. KS-WNK1, lacking an intact kinase domain, does not directly alter Kir1.1. Instead, KS-WNK1 negatively regulates L-WNK1 to release Kir1.1 from inhibition. Acute dietary potassium loading increases the relative abundance of KS-WNK1 to L-WNK1 transcript and protein in the kidney, indicating that physiologic up-regulation of Kir1.1 activity involves a WNK1 isoform switch and KS-WNK1-mediated release from L-WNK1 inhibition. Thus, these observations provide evidence for the physiological regulation of Na(+) and K(+) balance by a kinase isoform switch mechanism.
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA. jwade@umaryland.edu
authors.forename: James B
authors.initials: JB
authors.lastname: Wade
authors.forename: Liang
authors.initials: L
authors.lastname: Fang
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Dimin
authors.initials: D
authors.lastname: Li
authors.forename: Chao-Ling
authors.initials: CL
authors.lastname: Yang
authors.forename: Arohan R
authors.initials: AR
authors.lastname: Subramanya
authors.forename: Djikolngar
authors.initials: D
authors.lastname: Maouyo
authors.forename: Amanda
authors.initials: A
authors.lastname: Mason
authors.forename: David H
authors.initials: DH
authors.lastname: Ellison
authors.forename: Paul A
authors.initials: PA
authors.lastname: Welling
mesh_terms: D000818:Animals; D004594:Electrophysiology; D005786:Gene Expression Regulation; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism* / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014982:Xenopus laevis
chemical_list: D007527:Isoenzymes; D024661:Potassium Channels, Inwardly Rectifying; D017346:Protein Serine-Threonine Kinases; D011188:Potassium