Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/57317
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dc.contributor.authorMigliati, E.en
dc.contributor.authorMeurice, N.en
dc.contributor.authorDubois, P.en
dc.contributor.authorFang, J.en
dc.contributor.authorSomasekharan, S.en
dc.contributor.authorSpencer, E.en
dc.contributor.authorFlynn, G.en
dc.contributor.authorYool, A.en
dc.date.issued2009en
dc.identifier.citationMolecular Pharmacology, 2009; 76(1):105-112en
dc.identifier.issn0026-895Xen
dc.identifier.issn1521-0111en
dc.identifier.urihttp://hdl.handle.net/2440/57317-
dc.description.abstractAquaporin (AQP) water channels, essential for fluid homeostasis, are expressed in perivascular brain end-feet regions of astroglia (AQP4) and in choroid plexus (AQP1). At a high concentration, the loop diuretic bumetanide has been shown to reduce rat brain edema after ischemic stroke by blocking Na⁺-K⁺-2Cl⁻ cotransport. We hypothesized that an additional inhibition of AQP contributes to the protection. We show that osmotic water flux in AQP4-expressing Xenopus laevis oocytes is reduced by extracellular bumetanide (≥100 μM). The efficacy of block by bumetanide is increased by injection intracellularly. Forty-five synthesized bumetanide derivatives were tested on oocytes expressing human AQP1 and rat AQP4. Of these, one of the most effective was the 4-aminopyridine carboxamide analog, AqB013, which inhibits AQP1 and AQP4 (IC₅₀ ∼20 μM, applied extracellularly). The efficacy of block was enhanced by mutagenesis of intracellular AQP4 valine-189 to alanine (V189A, IC50 ∼8 μM), confirming the aquaporin as the molecular target of block. In silico docking of AqB013 supported an intracellular candidate binding site in rat AQP4 and suggested that the block involves occlusion of the AQP water pore at the cytoplasmic side. AqB013 at 2 μM had no effect, and 20 μM caused 20% block of human Na⁺-K⁺-2Cl⁻ cotransporter activity, in contrast to >90% block of the transporter by bumetanide. AqB013 did not affect X. laevis oocyte Cl- currents and did not alter rhythmic electrical conduction in an ex vivo gastric muscle preparation. The identification of AQP-selective pharmacological agents opens opportunities for breakthrough strategies in the treatment of edema and other fluid imbalance disorders.en
dc.description.statementofresponsibilityElton Migliati, Nathalie Meurice, Pascale DuBois, Jennifer S. Fang, Suma Somasekharan, Elizabeth Beckett, Gary Flynn and Andrea J. Yoolen
dc.language.isoenen
dc.publisherAmer Soc Pharmacology Experimental Therapeuticsen
dc.subjectBody Water; Animals; Xenopus laevis; Rats; Bumetanide; Diuretics; Binding Sites; Structure-Activity Relationship; Permeability; Sodium Potassium Chloride Symporter Inhibitors; Aquaporin 1; Aquaporin 4en
dc.titleInhibition of aquaporin-1 and aquaporin-4 water permeability by a derivative of the loop diuretic bumetanide acting at an internal pore-occluding binding siteen
dc.typeJournal articleen
dc.identifier.rmid0020091129en
dc.identifier.doi10.1124/mol.108.053744en
dc.identifier.pubid38560-
pubs.library.collectionMolecular and Biomedical Science publicationsen
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
dc.identifier.orcidYool, A. [0000-0003-1283-585X]en
Appears in Collections:Molecular and Biomedical Science publications

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