Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 10, Pages 4099-4104Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1216939110
Keywords
chloride efflux; ciliated cell; mouse; mucociliary clearance; submucosal gland
Categories
Funding
- Vaincre la Mucoviscidose
- Lions Club of Soissons
- 1 Euro contre le cancer
- Region Champagne-Ardenne
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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 alpha 7 nAChR as a key regulator of CFTR in the airways. The airway epithelium in alpha 7 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 Ca2+ in secretions, and a decreased mucus transport, all relevant to a deficient CFTR activity. Moreover, prolonged nicotine exposure mimics the absence of alpha 7 nAChR in mice or its inactivation in vitro in human airway epithelial cell cultures. The functional coupling of alpha 7 nAChR to CFTR occurs through Ca2+ entry and activation of adenylyl cyclases, protein kinase A, and PKC. alpha 7 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 alpha 7 nAChR in the regulation of CFTR function and in the pathogenesis of smoking-related chronic lung diseases.
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