Effects of lovastatin on trafficking of cystic fibrosis transmembrane conductance regulator in human tracheal epithelium

Ben Quan Shen, Jonathan H. Widdicombe, Randall J. Mrsny

Research output: Contribution to journalArticlepeer-review

Abstract

Genetic defects in the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel, cause cystic fibrosis. Most defective forms of CFTR show improper intracellular trafficking. Because isoprenylated, small GTP-binding proteins are involved in the vesicular trafficking of other integral membrane proteins, we have investigated the role of isoprenylation in the trafficking of CFTR to the apical membranes of primary cultures of human airway epithelium and of Calu-3 cells, a human lung carcinoma cell line. CFTR function was measured as short circuit current. 125I efflux, and conductance of cell sheets with permeabilized basolateral membranes. Lovastatin, an inhibitor of isoprenyl lipid biosynthesis, markedly inhibited all measures of CFTR function. The lovastatin, induced declines in CFTR function were corrected by the simultaneous addition of mevalonate or the isoprenyl lipids geranylgeranyl and farnesyl but not cholesterol. Lovastatin reduced total cellular CFTR as assessed by immunoprecipitation. Mevalonate or isoprenyl lipids protected CFTR levels from the actions of lovastatin. Together, these results suggest a role for isoprenyl lipids, presumably through the actions of small GTP-binding proteins, in the trafficking of CFTR to the apical membrane of human airway epithelium.

Original languageEnglish
Pages (from-to)25102-25106
Number of pages5
JournalJournal of Biological Chemistry
Volume270
Issue number42
DOIs
Publication statusPublished - 20 Oct 1995

Funding

FundersFunder number
Division of Intramural Research, Population Sciences Branch, National Heart, Lung and Blood Institute, Framingham, MA, USA.P50HL042368

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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