ArticleThe Journal of biological chemistry2013
N-terminal serine dephosphorylation is required for KCC3 cotransporter full activation by cell swelling.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 39 citations in OpenAlex.
- WNK-SPAK/OSR1 signaling pathway facilitates ictal activity via reduced neuronal chloride extrusion rate.bioRxiv : the preprint server for biology · 2026Article
- The role ofJournal of pharmaceutical analysis · 2023Review
- Chloride oscillation in pacemaker neurons regulates circadian rhythms through a chloride-sensing WNK kinase signaling cascade.Current biology : CB · 2022Article
- The Important Role of Ion Transport System in Cervical Cancer.International journal of molecular sciences · 2021Review
- Phospho-regulation, nucleotide binding and ion access control in potassium-chloride cotransporters.The EMBO journal · 2021Article
- SIRT7 modulates the stability and activity of the renal K-Cl cotransporter KCC4 through deacetylation.EMBO reports · 2021Article
- The structural basis of function and regulation of neuronal cotransporters NKCC1 and KCC2.Communications biology · 2021Article
- Targeting the WNK-SPAK/OSR1 Pathway and Cation-Chloride Cotransporters for the Therapy of Stroke.International journal of molecular sciences · 2021Review
- Coordinate adaptations of skeletal muscle and kidney to maintain extracellular [KAmerican journal of physiology. Cell physiology · 2020Article
- Distal convoluted tubule ClAmerican journal of physiology. Renal physiology · 2020Article
- Article
- Integrated K+ channel and K+Cl- cotransporter functions are required for the coordination of size and proportion during development.Developmental biology · 2019Article
- KJournal of hematology & oncology · 2019Review
- Physiological roles and molecular mechanisms of KThe Journal of physiology · 2019Review
- Phosphoregulation of the intracellular termini of KThe Journal of biological chemistry · 2018Article
- WNK Kinases in Development and Disease.Current topics in developmental biology · 2017Review
- With no lysine L-WNK1 isoforms are negative regulators of the K+-Cl- cotransporters.American journal of physiology. Cell physiology · 2016Article
- The Ste20 kinases SPAK and OSR1 travel between cells through exosomes.American journal of physiology. Cell physiology · 2016Article
- VRACs and other ion channels and transporters in the regulation of cell volume and beyond.Nature reviews. Molecular cell biology · 2016Review
- Revisiting the NaCl cotransporter regulation by with-no-lysine kinases.American journal of physiology. Cell physiology · 2015Review
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Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
Abstract
The K(+):Cl(-) cotransporter (KCC) activity is modulated by phosphorylation/dephosphorylation processes. In isotonic conditions, KCCs are inactive and phosphorylated, whereas hypotonicity promotes their dephosphorylation and activation. Two phosphorylation sites (Thr-991 and Thr-1048) in KCC3 have been found to be critical for its regulation. However, here we show that the double mutant KCC3-T991A/T1048A could be further activated by hypotonicity, suggesting that additional phosphorylation site(s) are involved. We observed that in vitro activated STE20/SPS1-related proline/alanine-rich kinase (SPAK) complexed to its regulatory MO25 subunit phosphorylated KCC3 at Ser-96 and that in Xenopus laevis oocytes Ser-96 of human KCC3 is phosphorylated in isotonic conditions and becomes dephosphorylated during incubation in hypotonicity, leading to a dramatic increase in KCC3 function. Additionally, WNK3, which inhibits the activity of KCC3, promoted phosphorylation of Ser-96 as well as Thr-991 and Thr-1048. These observations were corroborated in HEK293 cells stably transfected with WNK3. Mutation of Ser-96 alone (KCC3-S96A) had no effect on the activity of the cotransporter when compared with wild type KCC3. However, when compared with the double mutant KCC3-T991A/T1048A, the triple mutant KCC3-S96A/T991A/T1048A activity in isotonic conditions was significantly higher, and it was not further increased by hypotonicity or inhibited by WNK3. We conclude that serine residue 96 of human KCC3 is a third site that has to be dephosphorylated for full activation of the cotransporter during hypotonicity.
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