Evidence for multidrug resistance-1 P-glycoprotein-dependent regulation of cellular ATP permeability

R. M. Roman, N. Lomri, G. Braunstein, A. P. Feranchak, L. A. Simeoni, A. K. Davison, E. Mechetner, E. M. Schwiebert, J. G. Fitz

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

The mechanisms responsible for regulating epithelial ATP permeability and purinergic signaling are not well defined. Based on the observations that members of the ATP-binding cassette (ABC)1 family of proteins may contribute to ATP release, the purpose of these studies was to assess whether multidrug resistance-1 (MDR1) proteins are involved in ATP release from HTC hepatoma cells. Using a bioluminescence assay to detect extracellular ATP, increases in cell volume increased ATP release ̃3-fold. The MDR1 inhibitors cyclosporine A (10 μM) and verapramil (10 μM) inhibited ATP release by 69% and 62%, respectively (p < 0.001). Similarly, in whole-cell patch-clamp recordings, intracellular dialysis with C219 antibodies to inhibit MDR1 decreased ATP-dependent volume-sensitive Cl- current density from -33.1 ± 12.5 pA/pF to -2.0 ± 0.3 pA/pF (-80 reV, p 0.02). In contrast, overexpression of MDR1 in NIH 3T3 cells increased ATP release rates. Inhibition of ATP release by Gd3+ had no effect on transport of the MDR1 substrate rhodamine-123; and alteration of MDR1-substrate selectivity by mutation of G185 to V185 had no effect on ATP release. Since the effects of P-glycoproteins on ATP release can be dissociated from P-glycoprotein substrate transport, MDR1 is not likely to function as an ATP channel, but instead serves as a potent regulator of other cellular ATP transport pathways.

Original languageEnglish (US)
Pages (from-to)165-173
Number of pages9
JournalJournal of Membrane Biology
Volume183
Issue number3
DOIs
StatePublished - Oct 1 2001

Keywords

  • ABC protein
  • Cell volume
  • Cl channel
  • Liver
  • Purinergic receptor

ASJC Scopus subject areas

  • Biophysics
  • Physiology
  • Cell Biology

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    Roman, R. M., Lomri, N., Braunstein, G., Feranchak, A. P., Simeoni, L. A., Davison, A. K., Mechetner, E., Schwiebert, E. M., & Fitz, J. G. (2001). Evidence for multidrug resistance-1 P-glycoprotein-dependent regulation of cellular ATP permeability. Journal of Membrane Biology, 183(3), 165-173. https://doi.org/10.1007/s00232-001-0064-7