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Volume-activated Chloride Current Is Not Related to P-Glycoprotein Overexpression¹

Department of Molecular Pharmacology [Y-j. D., K. K., A. C. C., P. G.] and Divisions of Oncology and Clinical Pharmacology [G. C., G. E. D., B. I. S.], Stanford University, Stanford, California 94305; and Department of Medicine, Division of Immunology, University of California, Irvine, California 92717-4069 [S. G., S. V. G.]

It has been suggested that P-glycoprotein (P-gp), an ATP-dependent transporter responsible for classical multidrug resistance, is also a volume-regulated chloride channel. We reexamined this hypothesis by use of whole-cell patch clamp recordings of three matched pairs of cell lines, which were either drug-sensitive or drug-resistant due to P-gp overexpression. We demonstrate here that volume-regulated chloride-selective currents can be induced in cells with or without P-gp expression. Overexpression of either P-gp or cystic fibrosis transmembrane conductance regulator, the protein product of the CF gene and another member of the ATP-dependent transporters, is associated with a hypotonicity-induced, rapid onset, transient current prior to onset of the volume-sensitive chloride-selective current, an apparent nonspecific effect related to the overexpression of an integral membrane protein. These results suggest that there is no relationship between P-gp and the chloride channel activated by cell swelling.

¹ Supported by NIH Grant DK41324 (P. G.) and the Cystic Fibrosis Foundation (Y-j. D., K. K., A. C. C. and P. G.).

² Present address: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.

³ Supported by American Cancer Society Grant DHP-76E.

⁴ To whom requests for reprints should be addressed, at Department of Molecular Pharmacology, L-333, Stanford University, Stanford, CA 94305.

Received 7/11/94. Accepted 8/25/94.

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