title: Inhibition of CFTR Cl- channel function caused by enzymatic hydrolysis of sphingomyelin.
abstract: Numerous mutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR, a Cl(-) channel) disrupt salt and fluid transport and lead to the formation of thick mucus in patients' airways. Obstruction by mucus predisposes CF patients to chronic infections and inflammation, which become gradually harder to control and eventually fatal. Aggressive antibiotic therapy and supportive measures have dramatically lengthened CF patients' lives. Here, we report that sphingomyelinases (SMase) from human respiratory pathogens strongly inhibit CFTR function. The hydrolysis of sphingomyelin by SMase makes it more difficult to activate CFTR by phosphorylation of its regulatory domain. By inhibiting CFTR currents, SMase-producing respiratory tract bacteria may not only aggravate pulmonary infection in some CF patients but may also elicit a condition, analogous to CFTR deficiency, in non-CF patients suffering from bacterial lung infection.
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Yajamana
authors.initials: Y
authors.lastname: Ramu
authors.forename: Yanping
authors.initials: Y
authors.lastname: Xu
authors.forename: Zhe
authors.initials: Z
authors.lastname: Lu
mesh_terms: D000818:Animals; D001408:Bacillus anthracis / Q000201:enzymology; D002851:Chromatography, High Pressure Liquid; D003001:Cloning, Molecular; D016925:Corynebacterium pseudotuberculosis / Q000201:enzymology; D003550:Cystic Fibrosis / Q000209:etiology / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004594:Electrophysiology; D006801:Humans; D010766:Phosphorylation; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D013109:Sphingomyelins / Q000378:metabolism*; D013112:Spiders / Q000201:enzymology; D013211:Staphylococcus aureus / Q000201:enzymology
chemical_list: C505032:CFTR protein, human; D013109:Sphingomyelins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D013108:Sphingomyelin Phosphodiesterase