Dynasore, a small molecule inhibitor of dynamin, was used to probe the role of dynamin in the endocytosis of wild-type and mutant CFTR (cystic fibrosis transmembrane conductance regulator). Internalization of both wild-type and ‘temperature-corrected’ ΔF508 CFTR was markedly inhibited by a short exposure to dynasore, implicating dynamin as a key element in the endocytic internalization of both wild-type and mutant CFTR. The inhibitory effect of dynasore was readily reversible upon washout of dynasore from the growth media. Corr-4 ({2-(5-chloro-2-methoxy-phenylamino)-4′-methyl-[4,5′]-bithiazolyl-2′-yl}-phenyl-methanonone), a pharmacological corrector of ΔF508 CFTR biosynthesis, caused a marked increase in the cell surface expression of mutant CFTR. Co-incubation of ΔF508 CFTR expressing cells with Corr-4 and dynasore caused a significantly greater level of cell surface CFTR than that observed in the presence of Corr-4 alone. These results argue that inhibiting the endocytic internalization of mutant CFTR provides a novel therapeutic target for augmenting the benefits of small molecule correctors of mutant CFTR biosynthesis.
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Research Article|
July 15 2009
Dynasore inhibits removal of wild-type and ΔF508 cystic fibrosis transmembrane conductance regulator (CFTR) from the plasma membrane
Andrew Young;
Andrew Young
*Department of Physiology and Biophysics, Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, U.S.A.
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Martina Gentzsch;
Martina Gentzsch
†Cell and Developmental Biology, UNC Chapel Hill, 6109A Thurston-Bowles CB# 7248, Chapel Hill, NC 27599, U.S.A.
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Cynthia Y. Abban;
Cynthia Y. Abban
‡Department of Microbiology and Immunology, Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, U.S.A.
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Ying Jia;
Ying Jia
*Department of Physiology and Biophysics, Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, U.S.A.
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Patricio I. Meneses;
Patricio I. Meneses
‡Department of Microbiology and Immunology, Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, U.S.A.
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Robert J. Bridges;
Robert J. Bridges
*Department of Physiology and Biophysics, Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, U.S.A.
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Neil A. Bradbury
Neil A. Bradbury
1
*Department of Physiology and Biophysics, Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, U.S.A.
1To whom correspondence should be addressed (email neil.bradbury@rosalindfranklin.edu).
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Publisher: Portland Press Ltd
Received:
March 09 2009
Revision Received:
May 12 2009
Accepted:
May 14 2009
Accepted Manuscript online:
May 14 2009
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem J (2009) 421 (3): 377–385.
Article history
Received:
March 09 2009
Revision Received:
May 12 2009
Accepted:
May 14 2009
Accepted Manuscript online:
May 14 2009
Citation
Andrew Young, Martina Gentzsch, Cynthia Y. Abban, Ying Jia, Patricio I. Meneses, Robert J. Bridges, Neil A. Bradbury; Dynasore inhibits removal of wild-type and ΔF508 cystic fibrosis transmembrane conductance regulator (CFTR) from the plasma membrane. Biochem J 1 August 2009; 421 (3): 377–385. doi: https://doi.org/10.1042/BJ20090389
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