Volume-regulated chloride channels associated with the human multidrug-resistance P-glycoprotein

• Published in: Nature (London) 1992-02, Vol.355 (6363), p.830-833
• Main Authors: Valverde, Miguel A, DÍaz, Mario, Sepúlveda, Francisco V, Gill, Deborah R, Hyde, Stephen C, Higgins, Christopher F
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Analytical, structural and metabolic biochemistry; Animals; ATP; ATP-Binding Cassette, Sub-Family B, Member 1; Biological and medical sciences; Cellular biology; channels; chloride; Chloride Channels; Chlorides - metabolism; Colforsin - analogs & derivatives; Colforsin - pharmacology; dependent; Drug resistance; Drug Resistance - physiology; expression; Fundamental and applied biological sciences. Psychology; Genetic Vectors; Glycoproteins; Humanities and Social Sciences; Humans; Immunity (Disease); Ion Channels - physiology; Kinetics; letter; man; Membrane Glycoproteins - genetics; Membrane Glycoproteins - physiology; Membrane Potentials; Membrane Proteins - drug effects; Membrane Proteins - genetics; Membrane Proteins - physiology; Mice; Molecular Weight; multidisciplinary; NIH 3T3 cells; P-glucoprotein; Proteins; regulation; Science; Science (multidisciplinary); Transfection; Vaccinia virus - genetics; volume
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/355830a0

EXPRESSION of P-glycoprotein, the product of the MDR1 gene, confers multidrug resistance on cell lines and human tumours (reviewed in refs 1,2). P-glycoprotein (relative molecular mass 170,000) is an ATP-dependent, active transporter which pumps hydrophobic drugs out of cells 3 , but its normal physiological role is unknown. It is a member of the ABC (ATP-binding cassette) superfamily of transporters 4 , which includes many bacterial transport systems, the putative peptide transporter from the major histocompatibility locus, and the product of the cystic fibres is gene (the cystic fibrosis transmembrane regulator, CFTR). CFTR is located in the apical membranes of many secretory epithelia 5 and is associated with a cyclic AMP-regulated chloride channel 6–8 . At least two other chloride channels are present in epithelial cells, regulated by cell volume and by intracellular Ca 2+ , respectively 9,10 . Because of the structural and sequence similarities between P-glycoprotein and CFTR 4,11 , and because P-glycoprotein is abundant in many secretory epithelia 121–4 , we examined whether P-glycoprotein might be associated with one or other of these channels. We report here that expression of P-glycoprotein generates volume-regulated, ATP-dependent, chloride-selective channels, with properties similar to channels characterized previously in epithelial cells.