TY  - JOUR
U1  - Zeitschriftenartikel, wissenschaftlich - begutachtet (reviewed)
A1  - Lin, JinHeng
A1  - Gettings, Sean M.
A1  - Talbi, Khaoula
A1  - Schreiber, Rainer
A1  - Taggart, Michael J.
A1  - Preller, Matthias
A1  - Kunzelmann, Karl
A1  - Althaus, Mike
A1  - Gray, Michael A.
T1  - Pharmacological inhibitors of the cystic fibrosis transmembrane conductance regulator exert off-target effects on epithelial cation channels
JF  - Pflügers Archiv: European Journal of Physiology
N2  - 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.
KW  - Store-operated calcium entry
KW  - Off-target effects
KW  - Orai1
KW  - ENaC
KW  - In silico modelling
KW  - CFTR inhibitors
Y1  - 2023
UN  - https://nbn-resolving.org/urn:nbn:de:hbz:1044-opus-64572
SN  - 1432-2013
SS  - 1432-2013
U6  - https://doi.org/10.1007/s00424-022-02758-9
DO  - https://doi.org/10.1007/s00424-022-02758-9
PM  - 36205782
VL  - 475
IS  - 2
SP  - 167
EP  - 179
PB  - Springer
ER  -