title: Contribution of α7 nicotinic receptor to airway epithelium dysfunction under nicotine exposure.
abstract: Loss or dysfunction of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) leads to impairment of airway mucus transport and to chronic lung diseases resulting in progressive respiratory failure. Nicotinic acetylcholine receptors (nAChRs) bind nicotine and nicotine-derived nitrosamines and thus mediate many of the tobacco-related deleterious effects in the lung. Here we identify α7 nAChR as a key regulator of CFTR in the airways. The airway epithelium in α7 knockout mice is characterized by a higher transepithelial potential difference, an increase of amiloride-sensitive apical Na(+) absorption, a defective cAMP-dependent Cl(-) conductance, higher concentrations of Na(+), Cl(-), K(+), and Ca(2+) in secretions, and a decreased mucus transport, all relevant to a deficient CFTR activity. Moreover, prolonged nicotine exposure mimics the absence of α7 nAChR in mice or its inactivation in vitro in human airway epithelial cell cultures. The functional coupling of α7 nAChR to CFTR occurs through Ca(2+) entry and activation of adenylyl cyclases, protein kinase A, and PKC. α7 nAChR, CFTR, and adenylyl cyclase-1 are physically and functionally associated in a macromolecular complex within lipid rafts at the apical membrane of surface and glandular airway epithelium. This study establishes the potential role of α7 nAChR in the regulation of CFTR function and in the pathogenesis of smoking-related chronic lung diseases.
authors: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-Santé 903, 51092 Reims, France.
authors: Kamel
authors: K
authors: Maouche
authors: Kahina
authors: K
authors: Medjber
authors: Jean-Marie
authors: JM
authors: Zahm
authors: Franck
authors: F
authors: Delavoie
authors: Christine
authors: C
authors: Terryn
authors: Christelle
authors: C
authors: Coraux
authors: Stéphanie
authors: S
authors: Pons
authors: Isabelle
authors: I
authors: Cloëz-Tayarani
authors: Uwe
authors: U
authors: Maskos
authors: Philippe
authors: P
authors: Birembaut
authors: Jean-Marie
authors: JM
authors: Tournier
mesh_terms: D000818:Animals; D002038:Bungarotoxins / Q000633:toxicity; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D006801:Humans; D017136:Ion Transport; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009538:Nicotine / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D011978:Receptors, Nicotinic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000503:physiopathology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D002038:Bungarotoxins; C505032:CFTR protein, human; D002712:Chlorides; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D009538:Nicotine; D000242:Cyclic AMP; D002118:Calcium