Cigarette Smoke-Induced Ca2+ Release Leads to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Dysfunction [Molecular Bases of Disease]

January 21st, 2014 by Rasmussen, J. E., Sheridan, J. T., Polk, W., Davies, C. M., Tarran, R.

Chronic obstructive pulmonary disease (COPD) affects 64 million people and is currently the fourth leading cause of death worldwide. COPD includes both emphysema and chronic bronchitis, and in the case of chronic bronchitis represents an inflammatory response of the airways that is associated with mucus hypersecretion and small airways obstruction. Recently, it has emerged that cigarette smoke (CS) exposure leads to an inhibition of the CFTR Cl- channel, causing airway surface liquid (ASL) dehydration, which may play a role in the development of chronic bronchitis. CS rapidly clears CFTR from the plasma membrane and causes it to be deposited into aggresome-like compartments. However, little is known about the mechanism(s) responsible for the internalization of CFTR following CS exposure. Our studies revealed that CS triggered a rise in cytoplasmic Ca2+ that may have emanated from lysosomes. Furthermore, chelation of cytoplasmic Ca2+, but not inhibition of protein kinases/phosphatases prevented CS-induced CFTR internalization. The macrolide antibiotic bafilomycin A1 inhibited CS-induced Ca2+ release and prevented CFTR clearance from the plasma membrane, further linking cytoplasmic Ca2+ and CFTR internalization. We hypothesize that CS-induced Ca2+ release prevents normal sorting/degradation of CFTR and causes internalized CFTR to reroute to aggresomes. Our data provide mechanistic insight into the potentially deleterious effects of CS on airway epithelia and outline a hitherto unrecognized signaling event triggered by CS that may affect the long-term transition of the lung into a hyper-inflammatory/dehydrated environment.
  • Posted in Journal of Biological Chemistry, Publications
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