WNKs are potassium-sensitive kinases

With no lysine (K) (WNK) kinases regulate epithelial ion transport in the kidney to maintain homeostasis of electrolyte concentrations and blood pressure. Chloride ion directly binds WNK kinases to inhibit autophosphorylation and activation. Changes in extracellular potassium are thought to regulate...

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Bibliographic Details
Published in:American Journal of Physiology: Cell Physiology 2021-05, Vol.320 (5), p.C703-C721
Main Authors: Pleinis, John M, Norrell, Logan, Akella, Radha, Humphreys, John M, He, Haixia, Sun, Qifei, Zhang, Feng, Sosa-Pagan, Jason, Morrison, Daryl E, Schellinger, Jeffrey N, Jackson, Laurie K, Goldsmith, Elizabeth J, Rodan, Aylin R
Format: Article
Language:English
Subjects:
Alanine
Animals
Animals, Genetically Modified
Binding Sites
Blood pressure
Cell Line
Chloride
Chlorides
Chlorides - metabolism
Drosophila
Drosophila melanogaster - enzymology
Drosophila melanogaster - genetics
Drosophila Proteins - genetics
Drosophila Proteins - metabolism
Epithelial cells
Homeostasis
Hydrogen-Ion Concentration
Insects
Intracellular
Lysine
Malpighian tubules
Malpighian Tubules - enzymology
Mutation
Na+/K+-exchanging ATPase
Nutrient deficiency
Ouabain
Phosphorylation
Potassium
Potassium - metabolism
Proline
Protein Stability
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Rubidium
Sodium
Substrate Specificity
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Summary:With no lysine (K) (WNK) kinases regulate epithelial ion transport in the kidney to maintain homeostasis of electrolyte concentrations and blood pressure. Chloride ion directly binds WNK kinases to inhibit autophosphorylation and activation. Changes in extracellular potassium are thought to regulate WNKs through changes in intracellular chloride. Prior studies demonstrate that in some distal nephron epithelial cells, intracellular potassium changes with chronic low- or high-potassium diet. We, therefore, investigated whether potassium regulates WNK activity independent of chloride. We found decreased activity of WNK and mammalian WNK3 and WNK4 in fly Malpighian (renal) tubules bathed in high extracellular potassium, even when intracellular chloride was kept constant at either ∼13 mM or 26 mM. High extracellular potassium also inhibited chloride-insensitive mutants of WNK3 and WNK4. High extracellular rubidium was also inhibitory and increased tubule rubidium. The Na /K -ATPase inhibitor, ouabain, which is expected to lower intracellular potassium, increased tubule WNK activity. In vitro, potassium increased the melting temperature of WNK, WNK1, and WNK3 kinase domains, indicating ion binding to the kinase. Potassium inhibited in vitro autophosphorylation of WNK and WNK3, and also inhibited WNK3 and WNK4 phosphorylation of their substrate, Ste20-related proline/alanine-rich kinase (SPAK). The greatest sensitivity of WNK4 to potassium occurred in the range of 80-180 mM, encompassing physiological intracellular potassium concentrations. Together, these data indicate chloride-independent potassium inhibition of and mammalian WNK kinases through direct effects of potassium ion on the kinase.
ISSN:0363-6143
1522-1563
DOI:10.1152/ajpcell.00456.2020