Chromanol 293B, a blocker of the slow delayed rectifier K+ current (IKs), inhibits the CFTR Cl- current.
The cystic fibrosis transmembrane conductance regulator (CFTR) and the sulphonylurea receptor subunit (SUR) of the KATP channel are both members of the ATP-binding cassette (ABC) protein superfamily. Many compounds that open or block the KATP channel by binding to SUR also inhibit the CFTR Cl- current (ICFTR); an example in point is the chromanol-type KATP channel opener, cromakalim. The structurally related chromanol 293B (trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl-chromane), a blocker of the slow component of the delayed rectifier K+ current (IKs) in the heart, is also a weak inhibitor of KATP. This suggests that 293B may affect also ICFTR- We have addressed this question with human CFTR expressed in Xenopus oocytes. In two-electrode voltage-clamp experiments, 293B inhibited ICFTR with an IC50-value of 19 microM and Hill coefficient of 1.0; the inhibition was weakened by increasing concentrations of isobutyl-methylxanthine (IBMX). Patch-clamp recordings gave an IC50-value of 30 microM but showed a unusual variability in the sensitivity to 293B. The data show that 293B inhibits ICFTR and suggest that the mechanism of inhibition may depend on the phosphorylation state of the CFTR protein. The concentrations required for inhibition of ICFTR are three- to fivefold higher than those reported for inhibition of KvLQT1 + minK expressed in Xenopus oocytes. Since CFTR is expressed also in cardiac myocytes, the effects of 293B in these cells must be analysed with caution.
Bachmann
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Department of Pharmacology, University of Tübingen, Germany.
Quast
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Russ
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D000818:Animals; D002839:Chromans / Q000494:pharmacology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors*; D006801:Humans; D009865:Oocytes; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D013449:Sulfonamides / Q000494:pharmacology*; D014981:Xenopus
C505032:CFTR protein, human; D002839:Chromans; D026902:Potassium Channel Blockers; D013449:Sulfonamides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane