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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Gottesman, M. M. & Pastan, I. Trends pharmac. Sci. 9, 54–58 (1988).
Endicott, J. A. & Ling, V. A. Rev. Biochem. 58, 137–171 (1989).
Horio, M., Gottesman, M. M. & Pastan, I. Proc. natn. Acad. Sci. U.S.A. 85, 3580–3584 (1988).
Hyde, S. C. et al. Nature 346, 362–365 (1990).
Crawford, I. et al. Proc. natn. Acad. Sci. U.S.A. 88, 9262–9266 (1991).
Anderson, M. P. et al. Science 253, 202–205 (1991).
Kartner, N. et al. Cell 64, 681–692 (1991).
Tabcharani, J. A., Chang, X-B., Riordan, J. R. & Hanrahan, J. W. Nature 352, 628–631 (1991).
Wagner, J. A. et al. Nature 349, 793–796 (1991).
Worrell, R. T., Butt, A. G., Cliff, W. H. & Frizzell, R. A. Am. J. Physiol. 256, C1111–C1119 (1989).
Riordan, J. R. et al. Science 245, 1066–1073 (1989).
Thiebaut, F. et al. Proc. natn. Acad. Sci. U.S.A. 84, 7735–7738 (1987).
Cordon-Cardo, C. et al. J. Histochem. Cytochem. 38, 1277–1287 (1990).
Arceci, R. J., Croop, J. M., Horwitz, S. B. & Honsman, D. Proc. natn. Acad. Sci. U.S.A. 85, 4350–4354 (1988).
Morris, D. I., Robbins, J., Ruoho, A. E., Sutkowski, E. M. & Seaman, K. B. Biochemistry (in the press).
Morris, D. I., Speicher, L. A., Ruoho, A. E., Tew, K. D. & Seaman, K. B. J. biol. Chem. 266, 13377–13384 (1991).
Rivoltini, L. et al. Int. J. Cancer 46, 727–732 (1990).
McCann, J. D., Li, M. & Welsh, M. J. J. gen. Physiol. 94, 1015–1036 (1989).
Giraldez, F., Valverde, M. A. & Sepulveda, F. V. Biochim. Biophys. Acta 942, 353–356 (1988).
Okada, Y. & Hazama, A. News physiol. Sci. 4, 238–242 (1989).
Sheppard, D. N., Valverde, M. A., Giraldez, F. & Sepúlveda, F. V. J. Physiol. 433, 663–676 (1991).
Pastan, I. et al. Proc. natn. Acad Sci. U.S.A. 85, 4486–4490 (1988).
Shen, D.-W. et al. Science 232, 643–645 (1986).
Tanaka, S. et al. Biochem. biophys. Res. Commun. 166, 180–186 (1990).
Suzuki, S., Tachibana, M. & Kaneko, A. J. Physiol. 421, 645–662 (1990).
Baas, F. et al. Cancer Res. 50, 5392–5398 (1990).
Fuerst, T. R., Niles, E. G., Studier, F. W. & Moss, B. Proc. natn. Acad. Sci. U.S.A. 83, 8122–8126 (1986).
Felgner, P. L. et al. Proc. natn. Acad. Sci. U.S.A. 84, 7413–7417 (1987).
Karger, B. D. & Kornro, C. Focus 12, 25–27 (1990).
Laemmli, U. K. Nature 227, 680–685 (1970).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/355830a0
This article is cited by
-
Physiology of the volume-sensitive/regulatory anion channel VSOR/VRAC. Part 1: from its discovery and phenotype characterization to the molecular entity identification
The Journal of Physiological Sciences (2024)
-
Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis
Nature Communications (2022)
-
Biophysics and Physiology of the Volume-Regulated Anion Channel (VRAC)/Volume-Sensitive Outwardly Rectifying Anion Channel (VSOR)
Pflügers Archiv - European Journal of Physiology (2016)
-
VRAC: molecular identification as LRRC8 heteromers with differential functions
Pflügers Archiv - European Journal of Physiology (2016)
-
Chloride channels as drug targets
Nature Reviews Drug Discovery (2009)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.