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

B. Q. Shen, Jonathan Widdicombe, R. J. Mrsny

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 (US)
Pages (from-to)25102-25106
Number of pages5
JournalJournal of Biological Chemistry
Volume270
Issue number42
DOIs
StatePublished - 1995
Externally publishedYes

Fingerprint

Lovastatin
Cystic Fibrosis Transmembrane Conductance Regulator
Epithelium
Lipids
Mevalonic Acid
Membranes
GTP-Binding Proteins
Prenylation
Chloride Channels
Biosynthesis
Protein Transport
Immunoprecipitation
Cystic Fibrosis
Short circuit currents
Membrane Proteins
Cholesterol
Cells
Carcinoma
Cell Line
Lung

ASJC Scopus subject areas

  • Biochemistry

Cite this

Effects of lovastatin on trafficking of cystic fibrosis transmembrane conductance regulator in human tracheal epithelium. / Shen, B. Q.; Widdicombe, Jonathan; Mrsny, R. J.

In: Journal of Biological Chemistry, Vol. 270, No. 42, 1995, p. 25102-25106.

Research output: Contribution to journalArticle

@article{3b603af55b8e47bab9a9449b6ae44357,
title = "Effects of lovastatin on trafficking of cystic fibrosis transmembrane conductance regulator in human tracheal epithelium",
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.",
author = "Shen, {B. Q.} and Jonathan Widdicombe and Mrsny, {R. J.}",
year = "1995",
doi = "10.1074/jbc.270.42.25102",
language = "English (US)",
volume = "270",
pages = "25102--25106",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "42",

}

TY - JOUR

T1 - Effects of lovastatin on trafficking of cystic fibrosis transmembrane conductance regulator in human tracheal epithelium

AU - Shen, B. Q.

AU - Widdicombe, Jonathan

AU - Mrsny, R. J.

PY - 1995

Y1 - 1995

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0028792383&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028792383&partnerID=8YFLogxK

U2 - 10.1074/jbc.270.42.25102

DO - 10.1074/jbc.270.42.25102

M3 - Article

VL - 270

SP - 25102

EP - 25106

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 42

ER -