Carbon monoxide-releasing molecules inhibit the cystic fibrosis transmembrane conductance regulator Cl- channel
| Autor: | William J. Wilkinson, David N. Sheppard, Narattaphol Charoenphandhu, Bartholomew S.J. Harvey, Jia Liu, Walailak Jantarajit, Demi R S Ng, Mayuree Rodrat |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine congenital hereditary and neonatal diseases and abnormalities Physiology Allosteric regulation Cystic Fibrosis Transmembrane Conductance Regulator molecule 2 (CORM-2) Ivacaftor 03 medical and health sciences Adenosine Triphosphate Physiology (medical) carbon monoxide-releasing medicine Animals Humans Ion transporter Membrane potential Carbon Monoxide Ion Transport 030102 biochemistry & molecular biology biology Chemistry channel inhibition ivacaftor (VX-770) Depolarization CFTR chloride ion channel Cell Biology respiratory system Carbon monoxide-releasing molecules Cystic fibrosis transmembrane conductance regulator respiratory tract diseases CFTR potentiation 030104 developmental biology biology.protein Biophysics Ion Channel Gating Intracellular medicine.drug |
| Zdroj: | Rodrat, M, Jantarajit, W, Ng, D, Harvey, B S J, Liu, J, Wilkinson, W, Charoenphandhu, N & Sheppard, D N 2020, ' Carbon monoxide-releasing molecules inhibit the cystic fibrosis transmembrane conductance regulator Cl-channel ', AJP-Lung Cellular and Molecular Physiology, vol. 319, no. 6, pp. L997-L1009 . https://doi.org/10.1152/ajplung.00440.2019 |
| DOI: | 10.1152/ajplung.00440.2019 |
| Popis: | 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 RuCl3(100 μM) was without effect. CORM-2 predominantly inhibited CFTR by decreasing the frequency of channel openings and, hence, open probability ( Po). 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 Powithout 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 CFTRinh-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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|