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Research ArticleCellular and Molecular

Mutation-Induced Functional Alterations of CCR6

Bina Julian, Kevin Gao, Benjamin N. Harwood, Martin Beinborn and Alan S. Kopin
Journal of Pharmacology and Experimental Therapeutics January 2017, 360 (1) 106-116; DOI: https://doi.org/10.1124/jpet.116.237669
Bina Julian
Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts (B.J., K.G., B.N.H, M.B., A.S.K.); and Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts (B.J., M.B., A.S.K.)
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Kevin Gao
Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts (B.J., K.G., B.N.H, M.B., A.S.K.); and Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts (B.J., M.B., A.S.K.)
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Benjamin N. Harwood
Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts (B.J., K.G., B.N.H, M.B., A.S.K.); and Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts (B.J., M.B., A.S.K.)
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Martin Beinborn
Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts (B.J., K.G., B.N.H, M.B., A.S.K.); and Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts (B.J., M.B., A.S.K.)
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Alan S. Kopin
Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts (B.J., K.G., B.N.H, M.B., A.S.K.); and Program in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts (B.J., M.B., A.S.K.)
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Abstract

The Cys-Cys chemokine receptor 6 (CCR6) is a well-established modulator of inflammation. Although several genetic associations have been identified between CCR6 polymorphisms and immune system disorders (e.g., rheumatoid arthritis and Crohn’s disease), the pharmacological effects of naturally occurring missense mutations in this receptor have yet to be characterized. In this study, we initially assessed G protein–mediated signaling and observed that wild-type (WT) CCR6 exhibited ligand-independent activity. In addition, we found that the five most frequent CCR6 missense variants (A89T, A150V, R155W, G345S, and A369V) exhibited decreased basal and/or ligand induced Gαi protein signaling. To complement the study of these loss-of-function variants, we engineered a set of constitutively active CCR6 receptors. Selected mutations enhanced basal G protein–mediated signaling up to 3-fold relative to the WT value. Using a bioluminescence resonance energy transfer assay we investigated the ability of each naturally occurring and engineered CCR6 receptor mutant to recruit β-arrestin. In contrast to G protein–mediated signaling, β-arrestin mobilization was largely unperturbed by the naturally occurring loss-of-function CCR6 variants. Elevated recruitment of β-arrestin was observed in one of the engineered constitutively active mutants (T98P). Our results demonstrate that point mutations in CCR6 can result in either a gain or loss of receptor function. These observations underscore the need to explore how CCR6 natural variants may influence immune cell physiology and human disease.

Footnotes

    • Received September 9, 2016.
    • Accepted October 25, 2016.
  • dx.doi.org/10.1124/jpet.116.237669.

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

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 360 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 360, Issue 1
1 Jan 2017
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Research ArticleCellular and Molecular

Signaling Properties of CCR6 Variants

Bina Julian, Kevin Gao, Benjamin N. Harwood, Martin Beinborn and Alan S. Kopin
Journal of Pharmacology and Experimental Therapeutics January 1, 2017, 360 (1) 106-116; DOI: https://doi.org/10.1124/jpet.116.237669

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Research ArticleCellular and Molecular

Signaling Properties of CCR6 Variants

Bina Julian, Kevin Gao, Benjamin N. Harwood, Martin Beinborn and Alan S. Kopin
Journal of Pharmacology and Experimental Therapeutics January 1, 2017, 360 (1) 106-116; DOI: https://doi.org/10.1124/jpet.116.237669
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