ArticleThe Journal of biological chemistry2010
Differences in the large extracellular loop between the K(+)-Cl(-) cotransporters KCC2 and KCC4.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
27 citing papers in PubMed, 43 citations in OpenAlex.
- Regulated degradation of KCC2, a potassium-chloride co-transporter required for synaptic transmission and neurodevelopment.Channels (Austin, Tex.) · 2026Review
- Exploring the Cell Biological and Functional Effects of the First Disease Associated KCC1 Genetic Variant.Journal of cellular physiology · 2025Article
- Highly conserved ion binding sites are not all functionally relevant in mouse KCC4.Frontiers in molecular biosciences · 2025Article
- Pharmacology of Compounds Targeting Cation-Chloride Cotransporter Physiology.Handbook of experimental pharmacology · 2024Article
- Serine 937 phosphorylation enhances KCC2 activity and strengthens synaptic inhibition.Scientific reports · 2023Article
- KFrontiers in cellular neuroscience · 2023Article
- Cryo-EM structure of the human sodium-chloride cotransporter NCC.Science advances · 2022Article
- Molecular Mechanisms of Epilepsy: The Role of the Chloride Transporter KCC2.Journal of molecular neuroscience : MN · 2022Review
- Furosemide prevents membrane KCC2 downregulation during convulsant stimulation in the hippocampus.IBRO neuroscience reports · 2022Article
- High-Resolution Views and Transport Mechanisms of the NKCC1 and KCC Transporters.Journal of molecular biology · 2021Review
- Article
- Cryo-EM structures ofAmerican journal of physiology. Cell physiology · 2020Article
- Staurosporine and NEM mainly impair WNK-SPAK/OSR1 mediated phosphorylation of KCC2 and NKCC1.PloS one · 2020Article
- Reciprocal Regulation of KCC2 Trafficking and Synaptic Activity.Frontiers in cellular neuroscience · 2019Review
- Phosphoregulation of the intracellular termini of KThe Journal of biological chemistry · 2018Article
- Reply to The small molecule CLP257 does not modify activity of the KNature medicine · 2017Article
- Molecular cloning and biochemical characterization of two cation chloride cotransporter subfamily members of Hydra vulgaris.PloS one · 2017Article
- Impaired neuronal KCC2 function by biallelic SLC12A5 mutations in migrating focal seizures and severe developmental delay.Scientific reports · 2016Article
- Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures.Nature communications · 2015Article
- Neto2-null mice have impaired GABAergic inhibition and are susceptible to seizures.Frontiers in cellular neuroscience · 2015Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
K(+)Cl(-) cotransporters (KCCs) play fundamental physiological roles in processes such as inhibitory neurotransmission and cell volume regulation. Mammalian genomes encode four distinct KCC paralogs, which share basic transport characteristics but differ significantly in ion affinity, pharmacology, and relative sensitivity to cell volume. Studies to identify divergence in functional characteristics have thus far focused on the cytoplasmic termini. Here, we investigated sequence requirements of the large extracellular loop (LEL) for function in KCC2 and KCC4. Mutation of all four evolutionarily conserved cysteines abolished KCC2 transport activity. This behavior differs from that of its closest relative, KCC4, which is insensitive to this mutation. Chimeras supported the differences in the LEL of the two cotransporters, because swapping wild-type LEL resulted in functional KCC2 but rendered KCC4 inactive. Insertion of the quadruple cysteine substitution mutant of the KCC4 loop, which was functional in the parental isoform, abolished transport activity in KCC2. Dose-response curves of wild-type and chimeric KCCs revealed that the LEL contributes to the different sensitivity to loop diuretics; a KCC2 chimera containing the KCC4 LEL displayed an IC(50) of 396.5 mum for furosemide, which was closer to KCC4 (548.8 mum) than to KCC2 (184.4 mum). Cell surface labeling and immunocytochemistry indicated that mutations do not affect trafficking to the plasma membrane. Taken together, our results show a dramatic and unexpected difference in the sequence requirements of the LEL between the closely related KCC2 and KCC4. Furthermore, they demonstrate that evolutionarily highly conserved amino acids can have different functions within KCC members.
Indexed as
Identifiers
What OpenQuestion holds
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.