Home LiteratureArticle Details
PMID: 7678345 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The multidrug resistance (mdr1) gene product functions as an ATP channel.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 90 ·No. 1 ·1993-01-01 ·Pages 312-6

Abraham EH, Prat AG, Gerweck L, Seneveratne T, Arceci RJ, Kramer R, Guidotti G, Cantiello HF

Abstract

The multidrug resistance (mdr1) gene product, P-glycoprotein, is responsible for the ATP-dependent extrusion of a variety of compounds, including chemotherapeutic drugs, from cells. The data presented here show that cells with increased levels of the P-glycoprotein release ATP to the medium in proportion to the concentration of the protein in their plasma membrane. Furthermore, measurements of whole-cell and single-channel currents with patch-clamp electrodes indicate that the P-glycoprotein serves as an ATP-conducting channel in the plasma membrane. These findings suggest an unusual role for the P-glycoprotein.

Related Genes
mdr1
MeSH Terms
ATP Binding Cassette Transporter, Subfamily B, Member 1 Adenosine Triphosphate/metabolism Amino Acid Sequence Animals Antibodies CHO Cells Cell Membrane/physiology Cricetinae Drug Resistance/genetics Humans Ion Channels/physiology Lung Neoplasms Membrane Glycoproteins/genetics,physiology Mice Molecular Sequence Data Peptides/immunology Recombinant Fusion Proteins/metabolism Transfection Tumor Cells, Cultured
Chemicals
ATP Binding Cassette Transporter, Subfamily B, Member 1 Antibodies Ion Channels Membrane Glycoproteins Peptides Recombinant Fusion Proteins Adenosine Triphosphate
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Abraham E H
Department of Biochemistry and Molecular Biology, Harvard University, Cambridge, MA 02138.
Prat A G
Gerweck L
Seneveratne T
Arceci R J
Kramer R
Guidotti G
Cantiello H F
References (49)
49 references, click to expand
  1. Two bovine genes for mitochondrial ADP/ATP translocase expressed differences in various tissues.
    Biochemistry. 1989 Jan 24;28(2):866-73 PMID: 2540808
  2. Immunohistochemical detection of P-glycoprotein in human tumor cells with a low degree of drug resistance.
    Int J Cancer. 1989 Feb 15;43(2):340-3 PMID: 2563722
  3. Correlation of multidrug resistance with decreased drug accumulation, altered subcellular drug distribution, and increased P-glycoprotein expression in cultured SW-1573 human lung tumor cells.
    Cancer Res. 1989 Jun 1;49(11):2988-93 PMID: 2566376
  4. The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues.
    Mol Cell Biol. 1989 Mar;9(3):1346-50 PMID: 2471060
  5. Adenylyl cyclase amino acid sequence: possible channel- or transporter-like structure.
    Science. 1989 Jun 30;244(4912):1558-64 PMID: 2472670
  6. The function of Gp170, the multidrug resistance gene product, in rat liver canalicular membrane vesicles.
    J Biol Chem. 1989 Jul 15;264(20):11693-8 PMID: 2568355
  7. Localization of the ecto-ATPase (ecto-nucleotidase) in the rat hepatocyte plasma membrane. Implications for the functions of the ecto-ATPase.
    J Biol Chem. 1989 Aug 25;264(24):14403-7 PMID: 2527234
  8. Cloning and expression of a cDNA coding for a rat liver plasma membrane ecto-ATPase. The primary structure of the ecto-ATPase is similar to that of the human biliary glycoprotein I.
    J Biol Chem. 1989 Aug 25;264(24):14408-14 PMID: 2527235
  9. Is the multidrug transporter a flippase?
    Trends Biochem Sci. 1992 Jan;17(1):18-21 PMID: 1374941
  10. A nucleoside transporter is functionally linked to ectonucleotidases in rat liver canalicular membrane.
    J Biol Chem. 1992 May 15;267(14):9684-8 PMID: 1315767
  11. The biochemistry of P-glycoprotein-mediated multidrug resistance.
    Annu Rev Biochem. 1989;58:137-71 PMID: 2570548
  12. Separation of drug transport and chloride channel functions of the human multidrug resistance P-glycoprotein.
    Cell. 1992 Oct 2;71(1):23-32 PMID: 1382860
  13. Reconstitution of a bacterial periplasmic permease in proteoliposomes and demonstration of ATP hydrolysis concomitant with transport.
    Proc Natl Acad Sci U S A. 1989 Sep;86(18):6953-7 PMID: 2674940
  14. Discrete mutations introduced in the predicted nucleotide-binding sites of the mdr1 gene abolish its ability to confer multidrug resistance.
    Mol Cell Biol. 1989 Dec;9(12):5289-97 PMID: 2573836
  15. P-glycoprotein: multidrug-resistance and a superfamily of membrane-associated transport proteins.
    FASEB J. 1989 Dec;3(14):2583-92 PMID: 2574119
  16. Intracellular and extracellular levels of cyclic AMP during the cell cycle of Saccharomyces cerevisiae.
    Yeast. 1990 Jan-Feb;6(1):53-60 PMID: 2156391
  17. Structural model of ATP-binding proteins associated with cystic fibrosis, multidrug resistance and bacterial transport.
    Nature. 1990 Jul 26;346(6282):362-5 PMID: 1973824
  18. Sodium-adenosine cotransport in brush-border membranes from rabbit ileum.
    Am J Physiol. 1990 Sep;259(3 Pt 1):G504-10 PMID: 2399991
  19. The mitochondrial aspartate/glutamate and ADP/ATP carrier switch from obligate counterexchange to unidirectional transport after modification by SH-reagents.
    Biochim Biophys Acta. 1990 Oct 19;1028(3):268-80 PMID: 1977471
  20. G alpha i-3 regulates epithelial Na+ channels by activation of phospholipase A2 and lipoxygenase pathways.
    J Biol Chem. 1990 Dec 15;265(35):21624-8 PMID: 2174882
  21. Characteristics of receptor-operated and membrane potential-dependent ATP secretion from adrenal medullary chromaffin cells.
    Ann N Y Acad Sci. 1990;603:311-22; discussion 322-3 PMID: 2291530
  22. Multiple sodium-dependent nucleoside transport systems in bovine renal brush-border membrane vesicles.
    Biochem J. 1991 Feb 15;274 ( Pt 1):27-33 PMID: 2001243
  23. P-glycoprotein expression as a predictor of the outcome of therapy for neuroblastoma.
    N Engl J Med. 1991 Dec 5;325(23):1608-14 PMID: 1682809
  24. Translocation of ATP into the lumen of rough endoplasmic reticulum-derived vesicles and its binding to luminal proteins including BiP (GRP 78) and GRP 94.
    J Biol Chem. 1992 Feb 25;267(6):3983-90 PMID: 1740446
  25. Lipophilic cations: a group of model substrates for the multidrug-resistance transporter.
    Biochemistry. 1992 Feb 25;31(7):1992-8 PMID: 1371401
  26. P-glycoprotein. ATP hydrolysis by the N-terminal nucleotide-binding domain.
    J Biol Chem. 1992 Mar 5;267(7):4308-11 PMID: 1347041
  27. Expression of the human multidrug resistance cDNA in insect cells generates a high activity drug-stimulated membrane ATPase.
    J Biol Chem. 1992 Mar 5;267(7):4854-8 PMID: 1347044
  28. Volume-regulated chloride channels associated with the human multidrug-resistance P-glycoprotein.
    Nature. 1992 Feb 27;355(6363):830-3 PMID: 1371598
  29. Functional complementation of yeast ste6 by a mammalian multidrug resistance mdr gene.
    Science. 1992 Apr 10;256(5054):232-4 PMID: 1348873
  30. Regulation of plasma membrane recycling by CFTR.
    Science. 1992 Apr 24;256(5056):530-2 PMID: 1373908
  31. Reduced permeability in CHO cells as a mechanism of resistance to colchicine.
    J Cell Physiol. 1974 Feb;83(1):103-16 PMID: 4855907
  32. Functional polarity of the rat hepatocyte surface membrane. Isolation and characterization of plasma-membrane subfractions from the blood-sinusoidal, bile-Canalicular and contiguous surfaces of the hepatocyte.
    Biochem J. 1975 Feb;146(2):375-88 PMID: 125584
  33. Microdetermination of plasma ATP and creatine phosphate concentrations with a luminescence biometer.
    Clin Chem. 1977 Dec;23(12):2254-7 PMID: 923076
  34. Extrusion of cyclic AMP from pigeon erythrocytes.
    J Biol Chem. 1979 Oct 10;254(19):9714-20 PMID: 226526
  35. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches.
    Pflugers Arch. 1981 Aug;391(2):85-100 PMID: 6270629
  36. The molecular function of adrenal chromaffin granules: established facts and unresolved topics.
    Neuroscience. 1986 Jun;18(2):261-90 PMID: 2942794
  37. Mammalian multidrug resistance gene: complete cDNA sequence indicates strong homology to bacterial transport proteins.
    Cell. 1986 Nov 7;47(3):371-80 PMID: 3768958
  38. Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells.
    Cell. 1986 Nov 7;47(3):381-9 PMID: 2876781
  39. ATP-binding properties of P glycoprotein from multidrug-resistant KB cells.
    FASEB J. 1987 Jul;1(1):51-4 PMID: 2886389
  40. Cyclic AMP and other signals controlling cell development and differentiation in Dictyostelium.
    Annu Rev Biochem. 1987;56:853-79 PMID: 3039908
  41. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues.
    Proc Natl Acad Sci U S A. 1987 Nov;84(21):7735-8 PMID: 2444983
  42. Purification of the 170- to 180-kilodalton membrane glycoprotein associated with multidrug resistance. 170- to 180-kilodalton membrane glycoprotein is an ATPase.
    J Biol Chem. 1988 Jan 25;263(3):1454-8 PMID: 2891711
  43. The tissue dependent expression of hamster P-glycoprotein genes.
    FEBS Lett. 1988 Mar 14;229(2):329-32 PMID: 2894327
  44. Induction by verapamil of a rapid increase in ATP consumption in multidrug-resistant tumor cells.
    FASEB J. 1988 Apr;2(7):2278-82 PMID: 3350243
  45. ATP-dependent transport of vinblastine in vesicles from human multidrug-resistant cells.
    Proc Natl Acad Sci U S A. 1988 May;85(10):3580-4 PMID: 3368466
  46. ATP/Mg2+-dependent binding of vincristine to the plasma membrane of multidrug-resistant K562 cells.
    J Biol Chem. 1988 Aug 25;263(24):11887-91 PMID: 3165378
  47. The multidrug transporter, a double-edged sword.
    J Biol Chem. 1988 Sep 5;263(25):12163-6 PMID: 2900833
  48. Influence of extracellular pH on intracellular pH and cell energy status: relationship to hyperthermic sensitivity.
    Radiat Res. 1988 Nov;116(2):305-12 PMID: 3186938
  49. Characterization of the multidrug resistance protein expressed in cell clones stably transfected with the mouse mdr1 cDNA.
    Cancer Res. 1989 May 15;49(10):2729-33 PMID: 2565763
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.90.1.312
Published
1993-01-01
Pages
312-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC45650
Subset
IM
Grants
NCI NIH HHS · CA22860 · United States
NHLBI NIH HHS · HL08893 · United States
External Links
PubMed source DOI: 10.1073/pnas.90.1.312 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2