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Research ArticleArticle

Quantification of Gi-Mediated Inhibition of Adenylyl Cyclase Activity Reveals That UDP Is a Potent Agonist of the Human P2Y14 Receptor

Rhonda L. Carter, Ingrid P. Fricks, Matthew O. Barrett, Lauren E. Burianek, Yixing Zhou, Hyojin Ko, Arijit Das, Kenneth A. Jacobson, Eduardo R. Lazarowski and T. Kendall Harden
Molecular Pharmacology December 2009, 76 (6) 1341-1348; DOI: https://doi.org/10.1124/mol.109.058578
Rhonda L. Carter
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Ingrid P. Fricks
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Matthew O. Barrett
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Lauren E. Burianek
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Yixing Zhou
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Hyojin Ko
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Arijit Das
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Kenneth A. Jacobson
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Eduardo R. Lazarowski
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T. Kendall Harden
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Abstract

The P2Y14 receptor was initially identified as a G protein-coupled receptor activated by UDP-glucose and other nucleotide sugars. We have developed several cell lines that stably express the human P2Y14 receptor, allowing facile examination of its coupling to native Gi family G proteins and their associated downstream signaling pathways (J Pharmacol Exp Ther 330:162–168, 2009). In the current study, we examined P2Y14 receptor-dependent inhibition of cyclic AMP accumulation in human embryonic kidney (HEK) 293, C6 glioma, and Chinese hamster ovary (CHO) cells stably expressing this receptor. Not only was the human P2Y14 receptor activated by UDP-glucose, but it also was activated by UDP. The apparent efficacies of UDP and UDP-glucose were similar, and the EC50 values (74, 33, and 29 nM) for UDP-dependent activation of the P2Y14 receptor in HEK293, CHO, and C6 glioma cells, respectively, were similar to the EC50 values (323, 132, and 72 nM) observed for UDP-glucose. UDP and UDP-glucose also stimulated extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in P2Y14 receptor-expressing HEK293 cells but not in wild-type HEK293 cells. A series of analogs of UDP were potent P2Y14 receptor agonists, but the naturally occurring nucleoside diphosphates, CDP, GDP, and ADP exhibited agonist potencies over 100-fold less than that observed with UDP. Two UDP analogs were identified that selectively activate the P2Y14 receptor over the UDP-activated P2Y6 receptor, and these molecules stimulated phosphorylation of ERK1/2 in differentiated human HL-60 promyeloleukemia cells, which natively express the P2Y14 receptor but had no effect in wild-type HL-60 cells, which do not express the receptor. We conclude that UDP is an important cognate agonist of the human P2Y14 receptor.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of General Medicine [Grant GM38213]; the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL34322]; and by the Intramural Research Program of the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.058578

  • ABBREVIATIONS:

    P2Y14-R
    P2Y14 receptor
    P2Y6-R
    P2Y6 receptor
    hP2Y14-R
    human P2Y14 receptor
    P2Y14-HEK293 cells
    human embryonic kidney 293 cells stably expressing the human P2Y14 receptor
    P2Y14-C6 cells
    C6 rat glioma cells stably expressing the human P2Y14 receptor
    P2Y14-CHO cells
    Chinese hamster ovary cells stably expressing the human P2Y14 receptor
    DMEM
    Dulbecco's modified Eagle's medium
    DMSO
    dimethyl sulfoxide
    ERK
    extracellular signal-regulated kinase
    UDPβS
    uridine 5′-O-thiodiphosphate
    MAP
    mitogen-activated protein
    MRS2802
    α,β-difluoromethylene-UDP
    MRS2907
    2-thio-UDP-β-propyl ester
    GTPγS
    guanosine 5′-O-(3-thio)triphosphate
    GPCR
    G protein-coupled receptor.

    • Received June 12, 2009.
    • Accepted September 16, 2009.
  • © 2009 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 76 (6)
Molecular Pharmacology
Vol. 76, Issue 6
1 Dec 2009
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Research ArticleArticle

Quantification of Gi-Mediated Inhibition of Adenylyl Cyclase Activity Reveals That UDP Is a Potent Agonist of the Human P2Y14 Receptor

Rhonda L. Carter, Ingrid P. Fricks, Matthew O. Barrett, Lauren E. Burianek, Yixing Zhou, Hyojin Ko, Arijit Das, Kenneth A. Jacobson, Eduardo R. Lazarowski and T. Kendall Harden
Molecular Pharmacology December 1, 2009, 76 (6) 1341-1348; DOI: https://doi.org/10.1124/mol.109.058578

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Research ArticleArticle

Quantification of Gi-Mediated Inhibition of Adenylyl Cyclase Activity Reveals That UDP Is a Potent Agonist of the Human P2Y14 Receptor

Rhonda L. Carter, Ingrid P. Fricks, Matthew O. Barrett, Lauren E. Burianek, Yixing Zhou, Hyojin Ko, Arijit Das, Kenneth A. Jacobson, Eduardo R. Lazarowski and T. Kendall Harden
Molecular Pharmacology December 1, 2009, 76 (6) 1341-1348; DOI: https://doi.org/10.1124/mol.109.058578
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