Agonists that stimulate secretion promote the recruitment of CFTR into membrane lipid microdomains
| العنوان: | Agonists that stimulate secretion promote the recruitment of CFTR into membrane lipid microdomains |
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| المؤلفون: | Hsin Wei Tseng, Dusik Kim, Elvis Pandžić, John W. Hanrahan, Paul W. Wiseman, Asmahan Abu-Arish |
| المصدر: | The Journal of General Physiology |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Cystic Fibrosis, Physiology, Membrane lipids, Amitriptyline, Vasoactive intestinal peptide, Cystic Fibrosis Transmembrane Conductance Regulator, Apoptosis, News, Cell Line, Research News, 03 medical and health sciences, Membrane Lipids, 0302 clinical medicine, Membrane Microdomains, medicine, Humans, Secretion, Lipid raft, Research Articles, Mesna, biology, Chemistry, Lipid microdomain, Epithelial Cells, respiratory system, Cystic fibrosis transmembrane conductance regulator, digestive system diseases, Cell biology, respiratory tract diseases, Protein Transport, 030104 developmental biology, Sphingomyelin Phosphodiesterase, biology.protein, Motile cilium, lipids (amino acids, peptides, and proteins), Carbachol, Acid sphingomyelinase, 030217 neurology & neurosurgery, medicine.drug, Research Article, Signal Transduction, Vasoactive Intestinal Peptide |
| الوصف: | Little is known about how CFTR, the Cl− channel that is mutated in cystic fibrosis, interacts with lipids. Abu-Arish et al. show that agents that stimulate salt and fluid secretion reduce CFTR lateral mobility and promote its clustering into ceramide-rich platforms, thereby increasing its surface expression. 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 µm2) 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. |
| تدمد: | 1540-7748 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e2784da82b0869be2916e7d03a28b9b0 https://pubmed.ncbi.nlm.nih.gov/31076449 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e2784da82b0869be2916e7d03a28b9b0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15407748 |
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