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In Vitro Studies on the Mechanism of CFTR Inhibition by a Fungus‐derived Compound and Its Potential Anti‐diarrheal Application
Author(s) -
Akrimajirachoote Nattaphong,
Satitsri Saravut,
Rukachaisirikul Vatcharin,
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.821.4
Subject(s) - cystic fibrosis transmembrane conductance regulator , secretion , chloride channel , chemistry , protein kinase a , activator (genetics) , intracellular , cotransporter , secretory pathway , ampk , secretory protein , biochemistry , microbiology and biotechnology , kinase , biology , endoplasmic reticulum , organic chemistry , gene , golgi apparatus , sodium
Secretory diarrheas caused by enterotoxin‐producing bacteria are a major global health problem. Overactivation of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels play an important role in the pathogenesis of secretory diarrheas. Preliminary results in our laboratory found that the fungus‐derived N453 inhibited CFTR‐mediated Cl − secretion with a half maximal inhibitory concentration (IC 50 ) of ̴ 2 μM in intestinal epithelial (T84) cells. This study aimed to explore its underlying mechanisms and to demonstrate its anti‐diarrheal application. As analyzed by apical Cl − current measurement, pretreatment with phosphodiesterase and multi‐drug resistance protein 4 inhibitors did not affect the inhibitory effect of N453 on cAMP‐induced Cl − secretion T84 cells. In addition, N453 inhibited Cl − secretion induced by CPT‐cAMP (non‐hydrolyzable cAMP). These results suggest that CFTR inhibition by N453 does not involve alteration of intracellular cAMP levels. Moreover, N453 inhibited CFTR‐mediated Cl − transport induced by genistein (direct CFTR activator), suggesting that N453 might directly inhibit CFTR activity. Pretreatment with inhibitors of AMP‐activated protein kinase (AMPK) and protein phosphatase (PP), negative regulators of CFTR, did not affect the inhibitory effect of N453 on cAMP‐induced Cl − secretion, suggesting that CFTR inhibition by N453 is not resulted from activation of these negative regulators. Interestingly, N453 inhibited Cl − secretion induced by cholera and heat‐stable enterotoxins. Collectively, N453 derived from fungi acts as CFTR inhibitors, which may be beneficial for the treatment 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 Kasetsart Veterinary Development Funds. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .