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Research ArticleCellular and Molecular

Selected Melanocortin 1 Receptor Single-Nucleotide Polymorphisms Differentially Alter Multiple Signaling Pathways

J. R. Doyle, J. P. Fortin, M. Beinborn and A. S. Kopin
Journal of Pharmacology and Experimental Therapeutics August 2012, 342 (2) 318-326; DOI: https://doi.org/10.1124/jpet.112.194548
J. R. Doyle
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J. P. Fortin
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M. Beinborn
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A. S. Kopin
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Abstract

The melanocortin 1 receptor (MC1R) is a highly polymorphic G protein-coupled receptor, which is known to modulate pigmentation and inflammation. In the current study, we investigated the pharmacological effects of select single-nucleotide polymorphisms (SNPs) (V60L, R163Q, and F196L). After transient expression of MC1Rs in human embryonic kidney 293 cells, basal and ligand-induced cAMP signaling and mitogen-activated protein kinase (MAPK) activation were assessed by using luciferase reporter gene assays and Western blot analysis, respectively. All receptor variants showed decreased basal cAMP activity. With the V60L and F196L variants, the decrease in constitutive activity was attributable, at least in part, to a reduction in surface expression. The F196L variant also displayed a significant reduction in potency for both the peptide agonist α-melanocyte-stimulating hormone (α-MSH) and the small-molecule agonist 1-[1-(3-methyl-l-histidyl-O-methyl-d-tyrosyl)-4-phenyl-4-piperidinyl]-1-butanone (BMS-470539). In MAPK signaling assays, the F196L variant showed decreased phospho-extracellular signal-regulated kinase levels after stimulation with either α-MSH or BMS-470539. In contrast, the R163Q variant displayed a selective loss of α-MSH-induced MAPK activation; whereas responsiveness to the small-molecule agonist BMS-470539 was preserved. Further assessment of MC1R variants in A549 cells, an in vitro model of inflammation, revealed an enhanced inflammatory response resulting from expression of the F196L variant (versus the wild-type MC1R). This alteration in function was restored by treatment with BMS-470539. Overall, these studies illustrate novel signaling profiles linked to distinct MC1R SNPs. Furthermore, our investigations highlight the potential for small-molecule drugs to rescue the function of MC1R variants that show reduced basal and/or α-MSH stimulated activity.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK072497] and the National Institutes of Health National Heart Lung and Blood Institute [Grant T32 HL069770].

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

    http://dx.doi.org/10.1124/jpet.112.194548.

  • ABBREVIATIONS:

    MC1R
    melanocortin 1 receptor
    GPCR
    G protein-coupled receptor
    MAPK
    mitogen-activated protein kinase
    SNP
    single-nucleotide polymorphism
    α-MSH
    α-melanocyte-stimulating hormone
    TNFα
    tumor necrosis factor-α
    HA
    hemagglutinin
    CRE
    cAMP-response element
    Luc
    luciferase
    ELISA
    enzyme-linked immunosorbent assay
    HEK
    human embryonic kidney
    PBS
    phosphate-buffered saline
    ERK
    extracellular signal-regulated kinase
    NDP
    Nle4-d-Phe7
    NFκB
    nuclear factor κB
    TBST
    Tris-buffered saline/Tween 20
    WT
    wild type
    BMS-470539
    1-[1-(3-methyl-l-histidyl-O-methyl-d-tyrosyl)-4-phenyl-4-piperidinyl]-1-butanone.

  • Received March 20, 2012.
  • Accepted April 27, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 2
1 Aug 2012
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Research ArticleCellular and Molecular

Signaling of Melanocortin 1 Receptor Polymorphisms

J. R. Doyle, J. P. Fortin, M. Beinborn and A. S. Kopin
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 318-326; DOI: https://doi.org/10.1124/jpet.112.194548

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Research ArticleCellular and Molecular

Signaling of Melanocortin 1 Receptor Polymorphisms

J. R. Doyle, J. P. Fortin, M. Beinborn and A. S. Kopin
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 318-326; DOI: https://doi.org/10.1124/jpet.112.194548
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