ArticleThe Journal of biological chemistry2014
A novel regulatory locus of phosphorylation in the C terminus of the potassium chloride cotransporter KCC2 that interferes with N-ethylmaleimide or staurosporine-mediated activation.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 45 citations in OpenAlex.
- Enhancing KCC2 function reduces interictal activity and prevents seizures in temporal lobe epilepsy.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Highly conserved ion binding sites are not all functionally relevant in mouse KCC4.Frontiers in molecular biosciences · 2025Article
- Uncovering novel KCC2 regulatory motifs through a comprehensive transposon-based mutant library.Frontiers in molecular neuroscience · 2024Article
- Neuronal KActa pharmacologica Sinica · 2024Review
- Serine 937 phosphorylation enhances KCC2 activity and strengthens synaptic inhibition.Scientific reports · 2023Article
- KFrontiers in cellular neuroscience · 2023Article
- Structural Pharmacology of Cation-Chloride Cotransporters.Membranes · 2022Review
- SNAP23 regulates KCC2 membrane insertion and activity following mZnR/GPR39 activation in hippocampalneurons.iScience · 2022Article
- How Staying Negative Is Good for the (Adult) Brain: Maintaining Chloride Homeostasis and the GABA-Shift in Neurological Disorders.Frontiers in molecular neuroscience · 2022Review
- NKCC1 and KCC2: Structural insights into phospho-regulation.Frontiers in molecular neuroscience · 2022Review
- Contribution of Smoothened Receptor Signaling in GABAergic Neurotransmission and Chloride Homeostasis in the Developing Rodent Brain.Frontiers in physiology · 2021Review
- Staurosporine and NEM mainly impair WNK-SPAK/OSR1 mediated phosphorylation of KCC2 and NKCC1.PloS one · 2020Article
- Isolation and Characterization of Multi-Protein Complexes Enriched in the K-Cl Co-transporter 2 From Brain Plasma Membranes.Frontiers in molecular neuroscience · 2020Article
- Impaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathology.Science signaling · 2019Article
- Developmentally regulated KCC2 phosphorylation is essential for dynamic GABA-mediated inhibition and survival.Science signaling · 2019Article
- Reciprocal Regulation of KCC2 Trafficking and Synaptic Activity.Frontiers in cellular neuroscience · 2019Review
- Crossing the Chloride Channel: The Current and Potential Therapeutic Value of the Neuronal KBioMed research international · 2019Review
- Phosphoregulation of the intracellular termini of KThe Journal of biological chemistry · 2018Article
- Article
- Molecular architecture of potassium chloride co-transporter KCC2.Scientific reports · 2017Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The neuron-specific cation chloride cotransporter KCC2 plays a crucial role in hyperpolarizing synaptic inhibition. Transporter dysfunction is associated with various neurological disorders, raising interest in regulatory mechanisms. Phosphorylation has been identified as a key regulatory process. Here, we retrieved experimentally observed phosphorylation sites of KCC2 from public databases and report on the systematic analysis of six phosphorylated serines, Ser(25), Ser(26), Ser(937), Ser(1022), Ser(1025), and Ser(1026). Alanine or aspartate substitutions of these residues were analyzed in HEK-293 cells. All mutants were expressed in a pattern similar to wild-type KCC2 (KCC2(WT)). Tl(+) flux measurements demonstrated unchanged transport activity for Ser(25), Ser(26), Ser(1022), Ser(1025), and Ser(1026) mutants. In contrast, KCC2(S937D), mimicking phosphorylation, resulted in a significant up-regulation of transport activity. Aspartate substitution of Thr(934), a neighboring putative phosphorylation site, resulted in a comparable increase in KCC2 transport activity. Both KCC2(T934D) and KCC2(S937D) mutants were inhibited by the kinase inhibitor staurosporine and by N-ethylmaleimide, whereas KCC2(WT), KCC2(T934A), and KCC2(S937A) were activated. The inverse staurosporine effect on aspartate versus alanine substitutions reveals a cross-talk between different phosphorylation sites of KCC2. Immunoblot and cell surface labeling experiments detected no alterations in total abundance or surface expression of KCC2(T934D) and KCC2(S937D) compared with KCC2(WT). These data reveal kinetic regulation of transport activity by these residues. In summary, our data identify a novel key regulatory phosphorylation site of KCC2 and a functional interaction between different conformation-changing post-translational modifications. The action of pharmacological agents aimed to modulate KCC2 activity for therapeutic benefit might therefore be highly context-specific.
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