Academic Journal
Pharmacological inhibitors of the cystic fibrosis transmembrane conductance regulator exert off-target effects on epithelial cation channels
| العنوان: | Pharmacological inhibitors of the cystic fibrosis transmembrane conductance regulator exert off-target effects on epithelial cation channels |
|---|---|
| المؤلفون: | Lin, JinHeng, Gettings, Sean M., Talbi, Khaoula, Schreiber, Rainer, Taggart, Michael J., Preller, Matthias, Kunzelmann, Karl, Althaus, Mike, Gray, Michael A. |
| المصدر: | Pflügers Archiv: European Journal of Physiology ; ISSN 1432-2013 ; Pflugers Arch - Eur J Physiol 475, 167–179 (2023) |
| بيانات النشر: | Hochschule Bonn-Rhein-Sieg |
| سنة النشر: | 2023 |
| المجموعة: | pub H-BRS - Publication Server of Bonn-Rhein-Sieg University of Applied Sciences |
| مصطلحات موضوعية: | ddc:571 |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| Relation: | https://pub.h-brs.de/frontdoor/index/index/docId/6457; https://nbn-resolving.org/urn:nbn:de:hbz:1044-opus-64572; https://pub.h-brs.de/files/6457/s00424-022-02758-9.pdf |
| الاتاحة: | https://pub.h-brs.de/frontdoor/index/index/docId/6457 https://nbn-resolving.org/urn:nbn:de:hbz:1044-opus-64572 https://pub.h-brs.de/files/6457/s00424-022-02758-9.pdf |
| Rights: | info:eu-repo/semantics/openAccess ; https://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: | edsbas.93890794 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |