ArticleProceedings of the National Academy of Sciences of the United States of America2008
Regulation of NKCC2 by a chloride-sensing mechanism involving the WNK3 and SPAK kinases.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 125 papers.
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Who cites it
125 citing papers in PubMed, 217 citations in OpenAlex.
- Association of Serum Chloride Concentration With All-Cause and Cardiovascular Mortality in Patients Undergoing Peritoneal Dialysis: The Fukuoka Peritoneal Dialysis Registry.Kidney medicine · 2026Article
- The WNK-OXSR1 osmosensing pathway mediates intestinal regeneration via Hippo-YAP signaling.The EMBO journal · 2026Article
- Dietary potassium restriction causes hypercalciuria, hypocalcemia, and bone loss in male mice.JCI insight · 2026Article
- Decongestion in heart failure: medical and device therapies.Nature reviews. Cardiology · 2025Review
- Kinase interaction analysis predicts actions of the WNK-OSR1/SPAK pathway.Communications biology · 2025Article
- Impact of aldosterone deficiency on the development of diuretic resistance in mice.Pflugers Archiv : European journal of physiology · 2025Article
- SGLT2 Inhibitors Blunt Kidney Magnesium Wasting in Acute Cisplatin-Induced Hypomagnesemia with Effects on the Thick Ascending Limb and Distal Convoluted Tubule.Journal of the American Society of Nephrology : JASN · 2025Article
- TNF inhibits NKCC2 phosphorylation by a calcineurin-dependent pathway.American journal of physiology. Renal physiology · 2025Article
- Diuretic strategies in acute decompensated heart failure.Heart failure reviews · 2025Review
- The evolving concepts of KS-WNK1 effect on NCC activity.American journal of physiology. Renal physiology · 2025Review
- Function and regulation of the insect NaCCC2 sodium transport proteins.Comparative biochemistry and physiology. Part A, Molecular & integrative physiology · 2024Article
- Arginine vasopressin regulates the renal NaAmerican journal of physiology. Renal physiology · 2024Article
- The role of uromodulin in cardiovascular disease: a review.Frontiers in cardiovascular medicine · 2024Review
- Serum Chloride and Heart Failure.Kidney medicine · 2023Review
- Persistent Hypochloremia Is Associated with Adverse Prognosis in Patients Repeatedly Hospitalized for Heart Failure.Journal of clinical medicine · 2023Article
- Article
- Review
- The effects of nitric oxide and 8-iso-prostaglandin F2α on chloride absorption in cortical thick ascending limb.Kidney research and clinical practice · 2022Article
- Arterial Blood Pressure, Neuronal Excitability, Mineral Metabolism and Cell Volume Regulation Mechanisms Revealed byMembranes · 2022Article
- The Post-Translational Modification Networking in WNK-Centric Hypertension Regulation and Electrolyte Homeostasis.Biomedicines · 2022Review
65 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 6 institutions in 3 countries.
Funding
Abstract
The Na(+):K(+):2Cl(-) cotransporter (NKCC2) is the target of loop diuretics and is mutated in Bartter's syndrome, a heterogeneous autosomal recessive disease that impairs salt reabsorption in the kidney's thick ascending limb (TAL). Despite the importance of this cation/chloride cotransporter (CCC), the mechanisms that underlie its regulation are largely unknown. Here, we show that intracellular chloride depletion in Xenopus laevis oocytes, achieved by either coexpression of the K-Cl cotransporter KCC2 or low-chloride hypotonic stress, activates NKCC2 by promoting the phosphorylation of three highly conserved threonines (96, 101, and 111) in the amino terminus. Elimination of these residues renders NKCC2 unresponsive to reductions of [Cl(-)](i). The chloride-sensitive activation of NKCC2 requires the interaction of two serine-threonine kinases, WNK3 (related to WNK1 and WNK4, genes mutated in a Mendelian form of hypertension) and SPAK (a Ste20-type kinase known to interact with and phosphorylate other CCCs). WNK3 is positioned upstream of SPAK and appears to be the chloride-sensitive kinase. Elimination of WNK3's unique SPAK-binding motif prevents its activation of NKCC2, as does the mutation of threonines 96, 101, and 111. A catalytically inactive WNK3 mutant also completely prevents NKCC2 activation by intracellular chloride depletion. Together these data reveal a chloride-sensing mechanism that regulates NKCC2 and provide insight into how increases in the level of intracellular chloride in TAL cells, as seen in certain pathological states, could drastically impair renal salt reabsorption.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.