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TitleAgonists that stimulate secretion promote the recruitment of CFTR into membrane lipid microdomains.
Publication TypeJournal Article
Year of Publication2019
AuthorsAbu-Arish, Asmahan, Elvis Pandžić, Dusik Kim, Hsin Wei Tseng, Paul W. Wiseman, and John W. Hanrahan
JournalJ Gen Physiol
Volume151
Issue6
Pagination834-849
Date Published2019 Jun 03
ISSN1540-7748
Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is a tightly regulated anion channel that mediates secretion by epithelia and is mutated in the disease cystic fibrosis. CFTR forms macromolecular complexes with many proteins; however, little is known regarding its associations with membrane lipids or the regulation of its distribution and mobility at the cell surface. We report here that secretagogues (agonists that stimulate secretion) such as the peptide hormone vasoactive intestinal peptide (VIP) and muscarinic agonist carbachol increase CFTR aggregation into cholesterol-dependent clusters, reduce CFTR lateral mobility within and between membrane microdomains, and trigger the fusion of clusters into large (3.0 µm) ceramide-rich platforms. CFTR clusters are closely associated with motile cilia and with the enzyme acid sphingomyelinase (ASMase) that is constitutively bound on the cell surface. Platform induction is prevented by pretreating cells with cholesterol oxidase to disrupt lipid rafts or by exposure to the ASMase functional inhibitor amitriptyline or the membrane-impermeant reducing agent 2-mercaptoethanesulfonate. Platforms are reversible, and their induction does not lead to an increase in apoptosis; however, blocking platform formation does prevent the increase in CFTR surface expression that normally occurs during VIP stimulation. These results demonstrate that CFTR is colocalized with motile cilia and reveal surprisingly robust regulation of CFTR distribution and lateral mobility, most likely through autocrine redox activation of extracellular ASMase. Formation of ceramide-rich platforms containing CFTR enhances transepithelial secretion and likely has other functions related to inflammation and mucosal immunity.

DOI10.1085/jgp.201812143
Alternate JournalJ. Gen. Physiol.
PubMed ID31048413
PubMed Central IDPMC6572005