ArticleThe Journal of biological chemistry2012
Multiple evolutionarily conserved Di-leucine like motifs in the carboxyl terminus control the anterograde trafficking of NKCC2.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 31 citations in OpenAlex.
- Actin cytoskeleton and associated myosin motors within the renal epithelium.American journal of physiology. Renal physiology · 2024Review
- Review
- Pharmacology of Compounds Targeting Cation-Chloride Cotransporter Physiology.Handbook of experimental pharmacology · 2024Article
- Update on NKCC2 regulation in the thick ascending limb (TAL) by membrane trafficking, phosphorylation, and protein-protein interactions.Frontiers in physiology · 2024Review
- Systematic Assessment of Protein C-Termini Mutated in Human Disorders.Biomolecules · 2023Article
- Article
- Diacidic Motifs in the Carboxyl Terminus Are Required for ER Exit and Translocation to the Plasma Membrane of NKCC2.International journal of molecular sciences · 2022Article
- Golgi Alpha1,2-Mannosidase IA Promotes Efficient Endoplasmic Reticulum-Associated Degradation of NKCC2.Cells · 2021Article
- Differential Effects of STCH and Stress-Inducible Hsp70 on the Stability and Maturation of NKCC2.International journal of molecular sciences · 2021Article
- Conserved C-terminal motifs in odorant receptors instruct their cell surface expression and cAMP signaling.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- Molecular regulation of NKCC2 in blood pressure control and hypertension.Current opinion in nephrology and hypertension · 2019Review
- The carboxy-terminus, a key regulator of protein function.Critical reviews in biochemistry and molecular biology · 2019Review
- OS9 Protein Interacts with Na-K-2Cl Co-transporter (NKCC2) and Targets Its Immature Form for the Endoplasmic Reticulum-associated Degradation Pathway.The Journal of biological chemistry · 2016Article
- Impact of Hybrid and Complex N-Glycans on Cell Surface Targeting of the Endogenous Chloride Cotransporter Slc12a2.International journal of cell biology · 2015Article
- Localization and vasopressin regulation of the Na⁺-K⁺-2Cl⁻ cotransporter in the distal colonic epithelium.World journal of gastroenterology · 2014Article
- Annexin A2 mediates apical trafficking of renal Na⁺-K⁺-2Cl⁻ cotransporter.The Journal of biological chemistry · 2014Article
- Molecular and evolutionary insights into the structural organization of cation chloride cotransporters.Frontiers in cellular neuroscience · 2014Review
- COMMD1 interacts with the COOH terminus of NKCC1 in Calu-3 airway epithelial cells to modulate NKCC1 ubiquitination.American journal of physiology. Cell physiology · 2013Article
- The biogenesis of potassium transporters: implications of disease-associated mutations.Critical reviews in biochemistry and molecular biologyReview
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mutations in the apical Na-K-2Cl co-transporter, NKCC2, cause type I Bartter syndrome, a life-threatening kidney disease. Yet the mechanisms underlying the regulation of NKCC2 trafficking in renal cells are scarcely known. We previously showed that naturally occurring mutations depriving NKCC2 of its distal COOH-terminal tail and interfering with the (1081)LLV(1083) motif result in defects in the ER exit of the co-transporter. Here we show that this motif is necessary but not sufficient for anterograde trafficking of NKCC2. Indeed, we have identified two additional hydrophobic motifs, (1038)LL(1039) and (1048)LI(1049), that are required for ER exit and surface expression of the co-transporter. Double mutations of (1038)LL(1039) or (1048)LI(1049) to di-alanines disrupted glycosylation and cell surface expression of NKCC2, independently of the expression system. Pulse-chase analysis demonstrated that the absence of the terminally glycosylated form of NKCC2 was not due to reduced synthesis or increased rates of degradation of mutant co-transporters, but was instead caused by defects in maturation. Co-immunolocalization experiments revealed that (1038)AA(1039) and (1048)AA(1049) were trapped mainly in the ER as indicated by extensive co-localization with the ER marker calnexin. Remarkably, among several analyzed motifs present in the NKCC2 COOH terminus, only those required for ER exit and surface expression of NKCC2 are evolutionarily conserved in all members of the SLC12A family, a group of cation-chloride co-transporters that are targets of therapeutic drugs and mutated in several human diseases. Based upon these data, we propose abnormal anterograde trafficking as a common mechanism associated with mutations depriving NKCC2, and also all other members of the SLC12A family, of their COOH terminus.
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