Cystic fibrosis transmembrane conductance regulator (CFTR) represents the main cAMP-activated Cl- channel expressed in the apical membrane of serous epithelial cells. Both deficiency and overactivation of CFTR may cause fluid and salt secretion related diseases. The aim of this study was to identify natural compounds that are able to stimulate wild-type (wt) and F508 mutant CFTR channel activities in CFTR-expressing Fischer rat thyroid (FRT) cells. We found that dehydrocostuslactone [DHC, (3aS, 6aR, 9aR, 9bS)-decahydro-3,6,9-tris (methylene) azuleno [4,5-b] furan-2(3H)-one)] dose dependently potentiates both wt and F508 mutant CFTR-mediated iodide influx in cell-based fluorescent assays and CFTR-mediated Cl- currents in short-circuit current studies, and the activations could be reversed by the CFTR inhibitor CFTRinh-172. Maximal CFTR-mediated apical Cl- current secretion in CFTR-expressing FRT cells was stimulated by 100M DHC. Determination of intracellular cAMP content showed that DHC modestly but significantly increased cAMP level in FRT cells, but cAMP elevation effects contributed little to DHC-stimulated iodide influx. DHC also stimulated CFTR-mediated apical Cl- current secretion in FRT cells expressing F508-CFTR. Subsequent studies demonstrated that activation of CFTR by DHC is forskolin dependent. DHC represents a new class of CFTR potentiators that may have therapeutic potential in CFTR-related diseases.
[1]Liaoning Normal Univ, Sch Life Sci, Liaoning Prov Key Lab Biotechnol & Drug Discovery, Dalian 116081, Peoples R China.
[2]Jilin Univ, China Japan Union Hosp, Changchun 130033, Peoples R China.
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