WNK3

WNK3 is a serine/threonine WNK kinase that coordinates intracellular Cl^- handling by increasing NKCC1-mediated Cl^- influx and suppressing KCC-mediated Cl^- efflux^[1]. Mechanistically, WNK signaling activates SPAK/OSR1, which phosphorylates cation-chloride cotransporters to stimulate Na⁺-driven Cl^- importers and inhibit K⁺-driven Cl^- exporters^[2]. In ischemic stroke models, loss or inhibition of WNK3-SPAK/OSR1 signaling reduced infarct volume, cerebral edema, axonal demyelination, and improved neurological recovery^[3]. Compared with related isoforms, WNK3 and WNK4 show opposite sensitivity to cell volume and intracellular chloride concentration, defining isoform-specific control of CCC regulation^[4]. Human genetic evidence further links pathogenic WNK3 variants to X-linked intellectual disability, variable epilepsy, structural brain abnormalities, and impaired KCC2 phosphoregulation^[5]. In neuronal models, WNK3 regulates mature neuronal GABAergic tone and excitability through KCC2-dependent chloride control^[6][7]. For experimental applications, high-throughput screening identified WNK inhibitors, including quinoline compounds with greater potency toward WNK3 than WNK1, supporting isoform-focused tool development^[8].