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• W3087555502 endingPage "L1009" @default.
• W3087555502 startingPage "L997" @default.
• W3087555502 abstract "The gasotransmitter carbon monoxide (CO) regulates fluid and electrolyte movements across epithelial tissues. However, its action on anion channels is incompletely understood. Here, we investigate the direct action of CO on the cystic fibrosis transmembrane conductance regulator (CFTR) by applying CO-releasing molecules (CO-RMs) to the intracellular side of excised inside-out membrane patches from cells heterologously expressing wild-type human CFTR. Addition of increasing concentrations of tricarbonyldichlororuthenium(II) dimer (CORM-2) (1–300 μM) inhibited CFTR channel activity, whereas the control RuCl 3 (100 μM) was without effect. CORM-2 predominantly inhibited CFTR by decreasing the frequency of channel openings and, hence, open probability ( P o ). But, it also reduced current flow through open channels with very fast kinetics, particularly at elevated concentrations. By contrast, the chemically distinct CO-releasing molecule CORM-3 inhibited CFTR by decreasing P o without altering current flow through open channels. Neither depolarizing the membrane voltage nor raising the ATP concentration on the intracellular side of the membrane affected CFTR inhibition by CORM-2. Interestingly, CFTR inhibition by CORM-2, but not by CFTR inh -172, was prevented by prior enhancement of channel activity by the clinically approved CFTR potentiator ivacaftor. Similarly, when added after CORM-2, ivacaftor completely relieved CFTR inhibition. In conclusion, CORM-2 has complex effects on wild-type human CFTR consistent with allosteric inhibition and open-channel blockade. Inhibition of CFTR by CO-releasing molecules suggests that CO regulates CFTR activity and that the gasotransmitter has tissue-specific effects on epithelial ion transport. The action of ivacaftor on CFTR Cl − channels inhibited by CO potentially expands the drug’s clinical utility." @default.
• W3087555502 created "2020-09-25" @default.
• W3087555502 creator A5006306489 @default.
• W3087555502 creator A5020933651 @default.
• W3087555502 creator A5020933906 @default.
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• W3087555502 creator A5057117256 @default.
• W3087555502 creator A5061638973 @default.
• W3087555502 creator A5067821485 @default.
• W3087555502 creator A5089330933 @default.
• W3087555502 date "2020-12-01" @default.
• W3087555502 modified "2023-10-02" @default.
• W3087555502 title "Carbon monoxide-releasing molecules inhibit the cystic fibrosis transmembrane conductance regulator Cl⁻channel" @default.
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