ArticlePloS one2013
A trafficking-deficient mutant of KCC3 reveals dominant-negative effects on K-Cl cotransport function.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 29 citations in OpenAlex.
- SLC12A ion transporter mutations in sporadic and familial human congenital hydrocephalus.Molecular genetics & genomic medicine · 2019Trial
- Chasing the ghost in the code: highlighting the mystery of a rare genetic condition.American journal of physiology. Cell physiology · 2026Review
- Spectrum of dominant Charcot-Marie-Tooth disease due toJournal of neurology, neurosurgery, and psychiatry · 2026Article
- Exploring the Cell Biological and Functional Effects of the First Disease Associated KCC1 Genetic Variant.Journal of cellular physiology · 2025Article
- Pharmacology of Compounds Targeting Cation-Chloride Cotransporter Physiology.Handbook of experimental pharmacology · 2024Article
- The K-Cl cotransporter-3 in the mammalian kidney.Current opinion in nephrology and hypertension · 2023Review
- Cryo-EM structure of the human sodium-chloride cotransporter NCC.Science advances · 2022Article
- Structures and an activation mechanism of human potassium-chloride cotransporters.Science advances · 2020Article
- Article
- Cryo-EM structures ofAmerican journal of physiology. Cell physiology · 2020Article
- Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter.Science signaling · 2016Article
- Impaired neuronal KCC2 function by biallelic SLC12A5 mutations in migrating focal seizures and severe developmental delay.Scientific reports · 2016Article
- Kinase-KCC2 coupling: Cl- rheostasis, disease susceptibility, therapeutic target.Journal of neurophysiology · 2016Review
- K-Cl cotransporters, cell volume homeostasis, and neurological disease.Trends in molecular medicine · 2015Review
- Impact of Hybrid and Complex N-Glycans on Cell Surface Targeting of the Endogenous Chloride Cotransporter Slc12a2.International journal of cell biology · 2015Article
- The biogenesis of potassium transporters: implications of disease-associated mutations.Critical reviews in biochemistry and molecular biologyReview
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The K-Cl cotransporter (KCC) functions in maintaining chloride and volume homeostasis in a variety of cells. In the process of cloning the mouse KCC3 cDNA, we came across a cloning mutation (E289G) that rendered the cotransporter inactive in functional assays in Xenopus laevis oocytes. Through biochemical studies, we demonstrate that the mutant E289G cotransporter is glycosylation-deficient, does not move beyond the endoplasmic reticulum or the early Golgi, and thus fails to reach the plasma membrane. We establish through co-immunoprecipitation experiments that both wild-type and mutant KCC3 with KCC2 results in the formation of hetero-dimers. We further demonstrate that formation of these hetero-dimers prevents the proper trafficking of the cotransporter to the plasma membrane, resulting in a significant decrease in cotransporter function. This effect is due to interaction between the K-Cl cotransporter isoforms, as this was not observed when KCC3-E289G was co-expressed with NKCC1. Our studies also reveal that the glutamic acid residue is essential to K-Cl cotransporter function, as the corresponding mutation in KCC2 also leads to an absence of function. Interestingly, mutation of this conserved glutamic acid residue in the Na(+)-dependent cation-chloride cotransporters had no effect on NKCC1 function in isosmotic conditions, but diminished cotransporter activity under hypertonicity. Together, our data show that the glutamic acid residue (E289) is essential for proper trafficking and function of KCCs and that expression of a non-functional but full-length K-Cl cotransporter might results in dominant-negative effects on other K-Cl cotransporters.
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