title: Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis.
abstract: Dietary potassium deficiency activates thiazide-sensitive sodium chloride cotransport along the distal nephron. This may explain, in part, the hypertension and cardiovascular mortality observed in individuals who consume a low-potassium diet. Recent data suggest that plasma potassium affects the distal nephron directly by influencing intracellular chloride, an inhibitor of the with-no-lysine kinase (WNK)-Ste20p-related proline- and alanine-rich kinase (SPAK) pathway. As previous studies used extreme dietary manipulations, we sought to determine whether the relationship between potassium and NaCl cotransporter (NCC) is physiologically relevant and clarify the mechanisms involved. We report that modest changes in both dietary and plasma potassium affect NCC in vivo. Kinase assay studies showed that chloride inhibits WNK4 kinase activity at lower concentrations than it inhibits activity of WNK1 or WNK3. Also, chloride inhibited WNK4 within the range of distal cell chloride concentration. Mutation of a previously identified WNK chloride-binding motif converted WNK4 effects on SPAK from inhibitory to stimulatory in mammalian cells. Disruption of this motif in WNKs 1, 3, and 4 had different effects on NCC, consistent with the three WNKs having different chloride sensitivities. Thus, potassium effects on NCC are graded within the physiological range, which explains how unique chloride-sensing properties of WNK4 enable it to mediate effects of potassium on NCC in vivo.
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Terker
authors.affiliation: Department of Nephrology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Kayla J
authors.initials: KJ
authors.lastname: Erspamer
authors.affiliation: Molecular Physiology Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Universidad Nacional Autónoma de México, Mexico City, Mexico; Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Gamba
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA; VA Portland Health Care System, Portland, OR, USA.
authors.forename: Chao-Ling
authors.initials: CL
authors.lastname: Yang
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA; VA Portland Health Care System, Portland, OR, USA. Electronic address: ellisond@ohsu.edu.
authors.forename: David H
authors.initials: DH
authors.lastname: Ellison
mesh_terms: D000818:Animals; D002712:Chlorides / Q000378:metabolism*; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007686:Kidney Tubules, Distal / Q000166:cytology / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009399:Nephrons / Q000502:physiology; D010766:Phosphorylation / Q000235:genetics; D011188:Potassium / Q000097:blood* / Q000378:metabolism; D017419:Potassium, Dietary / Q000008:administration & dosage; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D064486:Solute Carrier Family 12, Member 3 / Q000378:metabolism*; D000076204:WNK Lysine-Deficient Protein Kinase 1
chemical_list: D002712:Chlorides; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D017419:Potassium, Dietary; D064486:Solute Carrier Family 12, Member 3; C499024:Prkwnk4 protein, mouse; C486407:Stk39 protein, mouse; D017346:Protein Serine-Threonine Kinases; C486409:STK39 protein, human; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human; C488586:WNK3 protein, human; C433806:WNK4 protein, human; C498744:Wnk1 protein, mouse; C507511:Wnk3 protein, mouse; D011188:Potassium
keywords: cell signaling; distal convoluted tubule; mineral metabolism; potassium channels; thiazide-sensitive NaCl cotransporter