ArticleThe Journal of biological chemistry2011
WNK2 kinase is a novel regulator of essential neuronal cation-chloride cotransporters.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 96 citations in OpenAlex.
- No lysine? No problem: the surprising roles of WNK kinases in physiology and disease.The Biochemical journal · 2026Review
- WNK2 oncogenicity revealed by the discovery and functional characterization of novel gene isoforms in MYD88 mutated Waldenström's Macroglobulinemia.Blood cancer journal · 2026Article
- Article
- KCC2 phosphorylation dynamics relate to oligomerization during development and after spinal cord injury.Frontiers in molecular neuroscience · 2026Article
- Chronic treatment with fluoxetine regulates mitochondrial features and plasticity-associated transcriptomic pathways in parvalbumin-positive interneurons of prefrontal cortex.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- Article
- Genome-Wide Association Study of Plasma Sodium Concentrations with and without Exposure to Thiazide Diuretics.Journal of the American Society of Nephrology : JASN · 2025Article
- Characterization and chemoproteomic profiling of protein O-GlcNAcylation in SOD1-G93A mouse model.Molecular medicine (Cambridge, Mass.) · 2025Article
- PAX6-WNK2 Axis Governs Corneal Epithelial Homeostasis.Investigative ophthalmology & visual science · 2024Article
- Alzheimer's disease rewires gene coexpression networks coupling different brain regions.NPJ systems biology and applications · 2024Article
- The brain-specific kinase LMTK3 regulates neuronal excitability by decreasing KCC2-dependent neuronal CliScience · 2024Article
- Germline mutations inJournal of medical genetics · 2023Article
- Arterial Blood Pressure, Neuronal Excitability, Mineral Metabolism and Cell Volume Regulation Mechanisms Revealed byMembranes · 2022Article
- CCT and CCT-Like Modular Protein Interaction Domains in WNK Signaling.Molecular pharmacology · 2022Review
- Molecular mechanisms for the modulation of blood pressure and potassium homeostasis by the distal convoluted tubule.EMBO molecular medicine · 2022Review
- The time course of molecular acclimation to seawater in a euryhaline fish.Scientific reports · 2021Article
- SIRT7 modulates the stability and activity of the renal K-Cl cotransporter KCC4 through deacetylation.EMBO reports · 2021Article
- Targeting the WNK-SPAK/OSR1 Pathway and Cation-Chloride Cotransporters for the Therapy of Stroke.International journal of molecular sciences · 2021Review
- WNK3 Maintains the GABAergic Inhibitory Tone, Synaptic Excitation and Neuronal ExcitabilityFrontiers in molecular neuroscience · 2021Article
- Contribution of Smoothened Receptor Signaling in GABAergic Neurotransmission and Chloride Homeostasis in the Developing Rodent Brain.Frontiers in physiology · 2021Review
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
NKCC1 and KCC2, related cation-chloride cotransporters (CCC), regulate cell volume and γ-aminobutyric acid (GABA)-ergic neurotranmission by modulating the intracellular concentration of chloride [Cl(-)]. These CCCs are oppositely regulated by serine-threonine phosphorylation, which activates NKCC1 but inhibits KCC2. The kinase(s) that performs this function in the nervous system are not known with certainty. WNK1 and WNK4, members of the WNK (with no lysine [K]) kinase family, either directly or via the downstream SPAK/OSR1 Ste20-type kinases, regulate the furosemide-sensitive NKCC2 and the thiazide-sensitive NCC, kidney-specific CCCs. What role the novel WNK2 kinase plays in this regulatory cascade, if any, is unknown. Here, we show that WNK2, unlike other WNKs, is not expressed in kidney; rather, it is a neuron-enriched kinase primarily expressed in neocortical pyramidal cells, thalamic relay cells, and cerebellar granule and Purkinje cells in both the developing and adult brain. Bumetanide-sensitive and Cl(-)-dependent (86)Rb(+) uptake assays in Xenopus laevis oocytes revealed that WNK2 promotes Cl(-) accumulation by reciprocally activating NKCC1 and inhibiting KCC2 in a kinase-dependent manner, effectively bypassing normal tonicity requirements for cotransporter regulation. TiO(2) enrichment and tandem mass spectrometry studies demonstrate WNK2 forms a protein complex in the mammalian brain with SPAK, a known phosphoregulator of NKCC1. In this complex, SPAK is phosphorylated at Ser-383, a consensus WNK recognition site. These findings suggest a role for WNK2 in the regulation of CCCs in the mammalian brain, with implications for both cell volume regulation and/or GABAergic signaling.
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Registered trials
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.