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Molecular Pharmacology

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Research ArticleArticle

Chaperoning of the A1-Adenosine Receptor by Endogenous Adenosine—An Extension of the Retaliatory Metabolite Concept

Justyna Kusek, Qiong Yang, Martin Witek, Christian W. Gruber, Christian Nanoff and Michael Freissmuth
Molecular Pharmacology January 2015, 87 (1) 39-51; DOI: https://doi.org/10.1124/mol.114.094045
Justyna Kusek
Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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Qiong Yang
Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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Martin Witek
Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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Christian W. Gruber
Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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Christian Nanoff
Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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Michael Freissmuth
Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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Abstract

Cell-permeable orthosteric ligands can assist folding of G protein–coupled receptors in the endoplasmic reticulum (ER); this pharmacochaperoning translates into increased cell surface levels of receptors. Here we used a folding-defective mutant of human A1-adenosine receptor as a sensor to explore whether endogenously produced adenosine can exert a chaperoning effect. This A1-receptor-Y288A was retained in the ER of stably transfected human embryonic kidney 293 cells but rapidly reached the plasma membrane in cells incubated with an A1 antagonist. This was phenocopied by raising intracellular adenosine levels with a combination of inhibitors of adenosine kinase, adenosine deaminase, and the equilibrative nucleoside transporter: mature receptors with complex glycosylation accumulated at the cell surface and bound to an A1-selective antagonist with an affinity indistinguishable from the wild-type A1 receptor. The effect of the inhibitor combination was specific, because it did not result in enhanced surface levels of two folding-defective human V2-vasopressin receptor mutants, which were susceptible to pharmacochaperoning by their cognate antagonist. Raising cellular adenosine levels by subjecting cells to hypoxia (5% O2) reproduced chaperoning by the inhibitor combination and enhanced surface expression of A1-receptor-Y288A within 1 hour. These findings were recapitulated for the wild-type A1 receptor. Taken together, our observations document that endogenously formed adenosine can chaperone its cognate A1 receptor. This results in a positive feedback loop that has implications for the retaliatory metabolite concept of adenosine action: if chaperoning by intracellular adenosine results in elevated cell surface levels of A1 receptors, these cells will be more susceptible to extracellular adenosine and thus more likely to cope with metabolic distress.

Footnotes

    • Received May 28, 2014.
    • Accepted October 29, 2014.
  • This work was supported by the doctoral program Cell Communication in Health and Disease, which was jointly funded by grants from the Austrian Science Fund/FWF – Fonds zur Förderung der wissenschaftlichen Forschung [W1205] and the Medical University of Vienna.

  • dx.doi.org/10.1124/mol.114.094045.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 87 (1)
Molecular Pharmacology
Vol. 87, Issue 1
1 Jan 2015
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Research ArticleArticle

Chaperoning of A1 Receptors by Endogenous Adenosine

Justyna Kusek, Qiong Yang, Martin Witek, Christian W. Gruber, Christian Nanoff and Michael Freissmuth
Molecular Pharmacology January 1, 2015, 87 (1) 39-51; DOI: https://doi.org/10.1124/mol.114.094045

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Research ArticleArticle

Chaperoning of A1 Receptors by Endogenous Adenosine

Justyna Kusek, Qiong Yang, Martin Witek, Christian W. Gruber, Christian Nanoff and Michael Freissmuth
Molecular Pharmacology January 1, 2015, 87 (1) 39-51; DOI: https://doi.org/10.1124/mol.114.094045
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