title: Nobiletin Stimulates Chloride Secretion in Human Bronchial Epithelia via a cAMP/PKA-Dependent Pathway.
abstract: OBJECTIVE
  Nobiletin, a citrus flavonoid isolated from tangerines, alters ion transport functions in intestinal epithelia, and has antagonistic effects on eosinophilic airway inflammation of asthmatic rats. The present study examined the effects of nobiletin on basal short-circuit current (I(SC)) in a human bronchial epithelial cell line (16HBE14o-), and characterized the signal transduction pathways that allowed nobiletin to regulate electrolyte transport.
  
  
  METHODS
  The I(SC) measurement technique was used for transepithelial electrical measurements. Intracellular calcium ([Ca(2+)]i) and cAMP were also quantified.
  
  
  RESULTS
  Nobiletin stimulated a concentration-dependent increase in I(SC), which was due to Cl- secretion. The increase in I(SC) was inhibited by a cystic fibrosis transmembrane conductance regulator inhibitor (CFTR(inh)-172), but not by 4,4'-diisothiocyano-stilbene-2,2'-disulphonic acid (DIDS), Chromanol 293B, clotrimazole, or TRAM-34. Nobiletin-stimulated I(SC) was also sensitive to a protein kinase A (PKA) inhibitor, H89, and an adenylate cyclase inhibitor, MDL-12330A. Nobiletin could not stimulate any increase in I(SC) in a cystic fibrosis (CF) cell line, CFBE41o-, which lacked a functional CFTR. Nobiletin stimulated a real-time increase in cAMP, but not [Ca(2+)]i.
  
  
  CONCLUSIONS
  Nobiletin stimulated transepithelial Cl- secretion across human bronchial epithelia. The mechanisms involved activation of adenylate cyclase- and cAMP/PKA-dependent pathways, leading to activation of apical CFTR Cl- channels.
authors: School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors: Yuan
authors: Y
authors: Hao
authors: Cindy S T
authors: CS
authors: Cheung
authors: Wallace C Y
authors: WC
authors: Yip
authors: Wing-hung
authors: WH
authors: Ko
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D047309:Flavones / Q000494:pharmacology*; D006801:Humans; D007097:Imines / Q000494:pharmacology; D017136:Ion Transport / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D002712:Chlorides; D047309:Flavones; D007097:Imines; D007546:Isoquinolines; D013449:Sulfonamides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C014925:RMI 12330A; C008661:nobiletin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002118:Calcium