ArticleFrontiers in cellular neuroscience2015
Regulated phosphorylation of the K-Cl cotransporter KCC3 is a molecular switch of intracellular potassium content and cell volume homeostasis.
Article in Frontiers in cellular neuroscience, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- NRBP1 pseudokinase binds to and activates the WNK pathway in response to osmotic stress.Science advances · 2025Article
- Genome sequencing provides novel insights into diadromous migration adaptations in the roughskin sculpin,ZooKeys · 2025Article
- The role ofJournal of pharmaceutical analysis · 2023Review
- The Important Role of Ion Transport System in Cervical Cancer.International journal of molecular sciences · 2021Review
- Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology.Nature communications · 2021Article
- Diseases caused by mutations in the NaAmerican journal of physiology. Cell physiology · 2021Review
- Phospho-regulation, nucleotide binding and ion access control in potassium-chloride cotransporters.The EMBO journal · 2021Article
- Temporal manipulation of KCC3 expression in juvenile or adult mice suggests irreversible developmental deficit in hereditary motor sensory neuropathy with agenesis of the corpus callosum.American journal of physiology. Cell physiology · 2021Article
- Targeting the WNK-SPAK/OSR1 Pathway and Cation-Chloride Cotransporters for the Therapy of Stroke.International journal of molecular sciences · 2021Review
- Osmotic Response of Dorsal Root Ganglion Neurons Expressing Wild-Type and Mutant KCC3 Transporters.Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology · 2020Article
- Article
- Modulation of brain cation-ClNature communications · 2020Article
- Integrated K+ channel and K+Cl- cotransporter functions are required for the coordination of size and proportion during development.Developmental biology · 2019Article
- The WNK-SPAK/OSR1 Kinases and the Cation-Chloride Cotransporters as Therapeutic Targets for Neurological Diseases.Aging and disease · 2019Review
- Water Homeostasis and Cell Volume Maintenance and Regulation.Current topics in membranes · 2018Review
- Temporal Lobe Epilepsy, Stroke, and Traumatic Brain Injury: Mechanisms of Hyperpolarized, Depolarized, and Flow-Through Ion Channels Utilized as Tri-Coordinate Biomarkers of Electrophysiologic Dysfunction.OBM neurobiology · 2018Article
- An Exploration of Charge Compensating Ion Channels across the Phagocytic Vacuole of Neutrophils.Frontiers in pharmacology · 2017Article
- Functional kinomics establishes a critical node of volume-sensitive cation-ClScientific reports · 2016Article
- Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter.Science signaling · 2016Article
- The biogenesis of potassium transporters: implications of disease-associated mutations.Critical reviews in biochemistry and molecular biologyReview
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7 authors.
Funding
Abstract
The defense of cell volume against excessive shrinkage or swelling is a requirement for cell function and organismal survival. Cell swelling triggers a coordinated homeostatic response termed regulatory volume decrease (RVD), resulting in K(+) and Cl(-) efflux via activation of K(+) channels, volume-regulated anion channels (VRACs), and the K(+)-Cl(-) cotransporters, including KCC3. Here, we show genetic alanine (Ala) substitution at threonines (Thr) 991 and 1048 in the KCC3a isoform carboxyl-terminus, preventing inhibitory phosphorylation at these sites, not only significantly up-regulates KCC3a activity up to 25-fold in normally inhibitory isotonic conditions, but is also accompanied by reversal of activity of the related bumetanide-sensitive Na(+)-K(+)-2Cl(-) cotransporter isoform 1 (NKCC1). This results in a rapid (<10 min) and significant (>90%) reduction in intracellular K(+) content (Ki) via both Cl-dependent (KCC3a + NKCC1) and Cl-independent [DCPIB (VRAC inhibitor)-sensitive] pathways, which collectively renders cells less prone to acute swelling in hypotonic osmotic stress. Together, these data demonstrate the phosphorylation state of Thr991/Thr1048 in KCC3a encodes a potent switch of transporter activity, Ki homeostasis, and cell volume regulation, and reveal novel observations into the functional interaction among ion transport molecules involved in RVD.
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