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Pharmacological inhibitors of the cystic fibrosis transmembrane conductance regulator exert off-target effects on epithelial cation channels

  • The cystic fibrosis transmembrane conductance regulator (CFTR) anion channel and the epithelial Na+ channel (ENaC) play essential roles in transepithelial ion and fluid transport in numerous epithelial tissues. Inhibitors of both channels have been important tools for defining their physiological role in vitro. However, two commonly used CFTR inhibitors, CFTRinh-172 and GlyH-101, also inhibit non-CFTR anion channels, indicating they are not CFTR specific. However, the potential off-target effects of these inhibitors on epithelial cation channels has to date not been addressed. Here, we show that both CFTR blockers, at concentrations routinely employed by many researchers, caused a significant inhibition of store-operated calcium entry (SOCE) that was time-dependent, poorly reversible and independent of CFTR. Patch clamp experiments showed that both CFTRinh-172 and GlyH-101 caused a significant block of Orai1-mediated whole cell currents, establishing that they likely reduce SOCE via modulation of this Ca2+ release-activated Ca2+ (CRAC) channel. In addition to off-target effects on calcium channels, both inhibitors significantly reduced human αβγ-ENaC-mediated currents after heterologous expression in Xenopus oocytes, but had differential effects on δβγ-ENaC function. Molecular docking identified two putative binding sites in the extracellular domain of ENaC for both CFTR blockers. Together, our results indicate that caution is needed when using these two CFTR inhibitors to dissect the role of CFTR, and potentially ENaC, in physiological processes.

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Document Type:Article
Author:JinHeng Lin, Sean M. Gettings, Khaoula Talbi, Rainer Schreiber, Michael J. Taggart, Matthias Preller, Karl Kunzelmann, Mike Althaus, Michael A. Gray
Parent Title (English):Pflügers Archiv: European Journal of Physiology
First Page:167
Last Page:179
Publishing Institution:Hochschule Bonn-Rhein-Sieg
Date of first publication:2022/10/07
Copyright:© The Author(s) 2022
Funding:This work was funded by a Newcastle University JJ Hunter Bequest Scholarship (JL, MJT, MAG) and the Cystic Fibrosis Trust (SRC013: MAG, KK).
Keyword:CFTR inhibitors; ENaC; In silico modelling; Off-target effects; Orai1; Store-operated calcium entry
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Institut für Technik, Ressourcenschonung und Energieeffizienz (TREE)
Institut für funktionale Gen-Analytik (IFGA)
Dewey Decimal Classification (DDC):5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 571 Physiologie und verwandte Themen
Fields of research:Institut für Technik, Ressourcenschonung und Energieeffizienz (TREE) / Arbeitsgruppe Computational Chemistry
Entry in this database:2022/10/14
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International