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Lookup NU author(s): JinHeng Lin, Sean Gettings, Professor Michael TaggartORCiD, Dr Mike Althaus, Dr Michael Gray
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022, The Author(s).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.
Author(s): Lin JH, Gettings SM, Talbi K, Schreiber R, Taggart MJ, Preller M, Kunzelmann K, Althaus M, Gray MA
Publication type: Article
Publication status: Published
Journal: Pflugers Archiv European Journal of Physiology
Year: 2023
Volume: 475
Pages: 167-179
Print publication date: 01/02/2023
Online publication date: 07/10/2022
Acceptance date: 03/10/2022
Date deposited: 25/10/2022
ISSN (print): 0031-6768
ISSN (electronic): 1432-2013
Publisher: Springer Science and Business Media Deutschland GmbH
URL: https://doi.org/10.1007/s00424-022-02758-9
DOI: 10.1007/s00424-022-02758-9
PubMed id: 36205782
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