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A Study on the Effect of N453 from Fungi on Inhibiting CFTR Chloride Channels in Intestinal Epithelial Cells
Author(s) -
Chutinun Onjira,
Akrimajirachoote Nattaphong,
Muanprasat Chatchai
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.821.6
Subject(s) - cystic fibrosis transmembrane conductance regulator , secretion , chloride channel , ussing chamber , apical membrane , cystic fibrosis , chemistry , pharmacology , microbiology and biotechnology , medicine , biochemistry , biology , membrane
Secretory diarrhea remains a global health problem, especially in developing countries. Cyclic AMP‐stimulated intestinal Cl − secretion plays a crucial role in pathogenesis of diarrheas including cholera and traveler's diarrhea. Inhibition of cAMP‐activated Cl − channel is considered as drug target for secretory diarrhea. The main objective of this study was to identify a novel inhibitor of the cystic fibrosis transmembrane conductance regulator (CFTR), cAMP‐activated Cl − channel, from a screen of fungal metabolites. A fungal derivative compound N453 was identified as an active compound that could inhibit cAMP‐activated Cl − secretion in intact T84 cells with a half maximal inhibitory concentration (IC 50 ) of ~ 0.78 μM in Ussing chamber experiments. Importantly, MTT assays revealed that N453 (up to100 μM) did not affect cell viability, suggesting that inhibition of cAMP‐activated Cl − current was not due to cytotoxic effect. In apical Cl − current analysis, N453 suppressed CFTR‐mediated apical Cl − current in a concentration‐dependent manner with IC 50 of ~ 2 μM. On the other hand, the Na + ‐K + ATPase activity was not affected by N453. Of interest, N453 concentration‐dependently inhibited basolateral cAMP‐activated K + channels with an IC 50 of ~ 23 μM. In conclusion, this study demonstrated that N453 inhibits Cl − secretion in intestinal epithelial cells, at least in part, by inhibiting CFTR‐mediated apical Cl − current and basolateral cAMP‐activated K + channels. N453 may be useful as potential therapy of secretory diarrheas. Support or Funding Information This work was supported by the NSTDA Chair Professor grant (the Fourth Grant) of the Crown Property Bureau Foundation, Faculty of Science Mahidol University, Faculty of Graduate Studies Mahidol University and Tonkla Ramathibodi. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .