ArticleThe Journal of biological chemistry2012
Loop diuretic and ion-binding residues revealed by scanning mutagenesis of transmembrane helix 3 (TM3) of Na-K-Cl cotransporter (NKCC1).
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 38 papers.
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Who cites it
38 citing papers in PubMed.
- Obesity and Heart Failure: Introducing the Theme.Journal of cardiovascular development and disease · 2026Review
- Furosemide Promotes Inflammatory Activation and Myocardial Fibrosis in Swine with Tachycardia-Induced Heart Failure.International journal of molecular sciences · 2025Article
- Structural bases for NaNature communications · 2024Article
- Navigating the multifaceted intricacies of the NaPhysiological reviews · 2024Review
- Involvement of sodium-glucose cotransporter-1 activities in maintaining oscillatory ClJournal of comparative physiology. B, Biochemical, systemic, and environmental physiology · 2024Article
- Latest Knowledge on the Role of Vitamin D in Hypertension.International journal of molecular sciences · 2023Review
- Diuretic resistance and the role of albumin in congestive heart failure.Drugs in context · 2023Review
- A Review of the Mechanism of Action of Drugs Used in Congestive Heart Failure in Pediatrics.Cureus · 2023Review
- Role of Monovalent Ions in the NKCC1 Inhibition Mechanism Revealed through Molecular Simulations.International journal of molecular sciences · 2022Article
- Cryo-EM structure of the human NKCC1 transporter reveals mechanisms of ion coupling and specificity.The EMBO journal · 2022Article
- Structural Pharmacology of Cation-Chloride Cotransporters.Membranes · 2022Review
- Inhibition mechanism of NKCC1 involves the carboxyl terminus and long-range conformational coupling.Science advances · 2022Article
- Structure of the human cation-chloride cotransport KCC1 in an outward-open state.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Structural basis for inhibition of the Cation-chloride cotransporter NKCC1 by the diuretic drug bumetanide.Nature communications · 2022Article
- Sequence analysis and function of mosquito aeCCC2 and Drosophila Ncc83 orthologs.Insect biochemistry and molecular biology · 2022Article
- Diuretic Resistance Associated With Heart Failure.Cureus · 2022Review
- The Acute Effects of Furosemide on Na-K-Cl Cotransporter-1, Fetuin-A and Pigment Epithelium-Derived Factor in the Guinea Pig Cochlea.Frontiers in molecular neuroscience · 2022Article
- Cation-coupled chloride cotransporters: chemical insights and disease implications.Trends in chemistry · 2021Review
- High-Resolution Views and Transport Mechanisms of the NKCC1 and KCC Transporters.Journal of molecular biology · 2021Review
- Molecular characteristics and physiological roles of NaJournal of cellular physiology · 2021Review
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Abstract
The Na-K-Cl cotransporter (NKCC) plays central roles in cellular chloride homeostasis and in epithelial salt transport, but to date little is known about the mechanism by which the transporter moves ions across the membrane. We examined the functional role of transmembrane helix 3 (TM3) in NKCC1 using cysteine- and tryptophan-scanning mutagenesis and analyzed our results in the context of a structural homology model based on an alignment of NKCC1 with other amino acid polyamine organocation superfamily members, AdiC and ApcT. Mutations of residues along one face of TM3 (Tyr-383, Met-382, Ala-379, Asn-376, Ala-375, Phe-372, Gly-369, and Ile-368) had large effects on translocation rate, apparent ion affinities, and loop diuretic affinity, consistent with a proposed role of TM3 in the translocation pathway. The prediction that Met-382 is part of an extracellular gate that closes to form an occluded state is strongly supported by conformational sensitivity of this residue to 2-(trimethylammonium)ethyl methanethiosulfonate, and the bumetanide insensitivity of M382W is consistent with tryptophan blocking entry of bumetanide into the cavity. Substitution effects on residues at the intracellular end of TM3 suggest that this region is also involved in ion coordination and may be part of the translocation pathway in an inward-open conformation. Mutations of predicted pore residues had large effects on binding of bumetanide and furosemide, consistent with the hypothesis that loop diuretic drugs bind within the translocation cavity. The results presented here strongly support predictions of homology models of NKCC1 and demonstrate important roles for TM3 residues in ion translocation and loop diuretic inhibition.
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