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

Abstract

EXPRESSION of P-glycoprotein, the product of theMDR1 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 cells3, but its normal physiological role is unknown. It is a member of the ABC (ATP-binding cassette) superfamily of transporters4, 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 epithelia5 and is associated with a cyclic AMP-regulated chloride channel6–8. At least two other chloride channels are present in epithelial cells, regulated by cell volume and by intracellular Ca2+, respectively9,10. Because of the structural and sequence similarities between P-glycoprotein and CFTR4,11, and because P-glycoprotein is abundant in many secretory epithelia121–4, 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.

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Valverde, M., DÍaz, M., Sepúlveda, F. et al. Volume-regulated chloride channels associated with the human multidrug-resistance P-glycoprotein. Nature 355, 830–833 (1992). https://doi.org/10.1038/355830a0

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