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Revisiting CFTR inhibition: a comparative study of CFTR inh ‐172 and GlyH ‐101 inhibitors
Author(s) -
Melis N,
Tauc M,
Coug M,
Bendahhou S,
Giuliano S,
Rubera I,
Duranton C
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12726
Subject(s) - cystic fibrosis transmembrane conductance regulator , chemistry , chloride channel , cystic fibrosis , context (archaeology) , conductance , viability assay , pharmacology , biochemistry , cell , biology , medicine , paleontology , mathematics , combinatorics , gene
Background and Purpose For decades, inhibitors of the cystic fibrosis transmembrane conductance regulator ( CFTR ) chloride channel have been used as tools to investigate the role and function of CFTR conductance in cystic fibrosis research. In the early 2000s, two new and potent inhibitors of CFTR , CFTR inh ‐172 and GlyH ‐101, were described and are now widely used to inhibit specifically CFTR . However, despite some evidence, the effects of both drugs on other types of Cl − ‐conductance have been overlooked. In this context, we explore the specificity and the cellular toxicity of both inhibitors in CFTR ‐expressing and non– CFTR ‐expressing cells. Experimental Approach Using patch‐clamp technique, we tested the effects of CFTR inh ‐172 and GlyH ‐101 inhibitors on three distinct types of Cl − currents: the CFTR ‐like conductance, the volume‐sensitive outwardly rectifying Cl − conductance ( VSORC ) and finally the Ca 2+ ‐dependent Cl − conductance ( CaCC ). We also explored the effect of both inhibitors on cell viability using live/dead and cell proliferation assays in two different cell lines. Key Results We confirmed that these two compounds were potent inhibitors of the CFTR ‐mediated Cl − conductance. However, GlyH ‐101 also inhibited the VSORC conductance and the CaCC at concentrations used to inhibit CFTR . The CFTR inh ‐172 did not affect the CaCC but did inhibit the VSORC, at concentrations higher than 5 µM. Neither inhibitor (20 µM; 24 h exposure) affected cell viability, but both were cytotoxic at higher concentrations. Conclusions and Implications Both inhibitors affected Cl − conductances apart from CFTR. Our results provided insights into their use in mouse models.