2024
Structural bases for Na+-Cl− cotransporter inhibition by thiazide diuretic drugs and activation by kinases
Zhao Y, Schubert H, Blakely A, Forbush B, Smith M, Rinehart J, Cao E. Structural bases for Na+-Cl− cotransporter inhibition by thiazide diuretic drugs and activation by kinases. Nature Communications 2024, 15: 7006. PMID: 39143061, PMCID: PMC11324901, DOI: 10.1038/s41467-024-51381-y.Peer-Reviewed Original ResearchConceptsNa+-Cl- cotransporterFamilial hyperkalemic hypertensionRenal salt retentionThiazide diuretic drugsNa+-Cl-Cotransporter inhibitionNCC activitySalt reabsorptionDiuretic drugsBlood pressureBalanced electrolyteTreat hypertensionIon translocation pathwayIon translocationThiazideHypertensionSalt retentionOrthosteric siteCo-structureCarboxyl-terminal domainKinase cascadeEdemaChlorthalidoneCotransporterTranslocation
2022
Structural basis for inhibition of the Cation-chloride cotransporter NKCC1 by the diuretic drug bumetanide
Zhao Y, Roy K, Vidossich P, Cancedda L, De Vivo M, Forbush B, Cao E. Structural basis for inhibition of the Cation-chloride cotransporter NKCC1 by the diuretic drug bumetanide. Nature Communications 2022, 13: 2747. PMID: 35585053, PMCID: PMC9117670, DOI: 10.1038/s41467-022-30407-3.Peer-Reviewed Original ResearchConceptsTranslocation pathwayElectron cryo-microscopy structureC-terminal domainIon translocation pathwayCation-chloride cotransporters NKCC1Transmembrane domainCotransporter NKCC1C-terminal domain interactionsStructural basisDomain interactionsRenal salt reabsorptionDomain associationConformational changesFunctional studiesIon translocationElectroneutral symportCell membraneNKCC1PathwayNKCC2DomainSalt reabsorptionTransmembraneTranslocationTransporters
2012
Loop Diuretic and Ion-binding Residues Revealed by Scanning Mutagenesis of Transmembrane Helix 3 (TM3) of Na-K-Cl Cotransporter (NKCC1)*
Somasekharan S, Tanis J, Forbush B. Loop Diuretic and Ion-binding Residues Revealed by Scanning Mutagenesis of Transmembrane Helix 3 (TM3) of Na-K-Cl Cotransporter (NKCC1)*. Journal Of Biological Chemistry 2012, 287: 17308-17317. PMID: 22437837, PMCID: PMC3366785, DOI: 10.1074/jbc.m112.356014.Peer-Reviewed Original ResearchConceptsTransmembrane helix 3Na-K-Cl cotransporterTranslocation pathwayHelix 3Homology modelTryptophan-scanning mutagenesisMutation of residuesStructural homology modelEpithelial salt transportExtracellular gateCellular chloride homeostasisScanning mutagenesisOpen conformationIntracellular endPore residuesFunctional roleIon translocationTranslocation rateResiduesMutagenesisCentral roleChloride homeostasisMutationsPathwayLarge effect
1998
Mutagenic Mapping of the Na-K-Cl Cotransporter for Domains Involved in Ion Transport and Bumetanide Binding
Isenring P, Jacoby S, Chang J, Forbush B. Mutagenic Mapping of the Na-K-Cl Cotransporter for Domains Involved in Ion Transport and Bumetanide Binding. The Journal Of General Physiology 1998, 112: 549-558. PMID: 9806964, PMCID: PMC2229443, DOI: 10.1085/jgp.112.5.549.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesBumetanideCarrier ProteinsCells, CulturedChloridesDiureticsHumansKidneyKineticsMutagenesis, Site-DirectedOligonucleotide ProbesPotassiumProtein Structure, TertiaryRecombinant Fusion ProteinsRubidium RadioisotopesSharksSodiumSodium-Potassium-Chloride SymportersSpecies Specificity
1987
Na,K,Cl-cotransport system: characterization by bumetanide binding and photolabelling.
Haas M, Forbush B. Na,K,Cl-cotransport system: characterization by bumetanide binding and photolabelling. Kidney International Supplement 1987, 23: s134-43. PMID: 3481640.Peer-Reviewed Original ResearchPhotolabeling of a 150-kDa (Na + K + Cl) cotransport protein from dog kidney with a bumetanide analogue
Haas M, Forbush B. Photolabeling of a 150-kDa (Na + K + Cl) cotransport protein from dog kidney with a bumetanide analogue. American Journal Of Physiology 1987, 253: c243-c252. PMID: 3618761, DOI: 10.1152/ajpcell.1987.253.2.c243.Peer-Reviewed Original ResearchConceptsKidney cortexBinding to kidney membranesDog kidney cortexSite of actionCotransporter proteinApical membraneAscending limbBumetanideCotransport systemHenle's loopEpithelial cellsPhotolysis mediumKidney membranesK 1/2Mammalian kidneyCrude membranesBenzophenone analoguesKidneyDog kidneyPresence of NaCortexPhotolysisSucrose density gradientsMolecular mass proteinsDogs
1986
[3H]bumetanide binding to duck red cells. Correlation with inhibition of (Na + K + 2Cl) co-transport.
Haas M, Forbush B. [3H]bumetanide binding to duck red cells. Correlation with inhibition of (Na + K + 2Cl) co-transport. Journal Of Biological Chemistry 1986, 261: 8434-8441. PMID: 3013852, DOI: 10.1016/s0021-9258(19)83931-5.Peer-Reviewed Original ResearchConceptsDuck red cellsExtracellular sodiumRed cellsCo-transportDog kidney outer medullaBinding of [3H]bumetanideConcentration of extracellular sodiumIncreased extracellular sodiumPresence of norepinephrineCo-transport systemBumetanide inhibitionKidney outer medullaOuter medullaBiphasic effectInhibition of influxCell shrinkageHalf-maximalSaturable bindingBumetanideInhibit bindingCell typesSaturable mannerNorepinephrineInfluxBinding to membranes
1983
[3H]bumetanide binding to membranes isolated from dog kidney outer medulla. Relationship to the Na,K,Cl co-transport system.
Forbush B, Palfrey H. [3H]bumetanide binding to membranes isolated from dog kidney outer medulla. Relationship to the Na,K,Cl co-transport system. Journal Of Biological Chemistry 1983, 258: 11787-11792. PMID: 6619143, DOI: 10.1016/s0021-9258(17)44299-2.Peer-Reviewed Original ResearchConceptsOuter medullaCl- co-transport systemDog kidney outer medullaCl- cotransport systemLoop of HenleCo-transport systemLoop diureticsBasolateral membraneKidney outer medullaProximal tubulesAscending limbLuminal membraneCotransport systemKidney cortexMedullaKidney membranesBrush borderCo-transportCrude membranesKidneyDog kidneyBinding to membranesBinding activityGradient centrifugation