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Rapid CommunicationAccelerated Communication

Design and Functional Characterization of a Novel, Arrestin-Biased Designer G Protein-Coupled Receptor

Ken-ichiro Nakajima and Jürgen Wess
Molecular Pharmacology October 2012, 82 (4) 575-582; DOI: https://doi.org/10.1124/mol.112.080358
Ken-ichiro Nakajima
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
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Jürgen Wess
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
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Abstract

Mutational modification of distinct muscarinic receptor subtypes has yielded novel designer G protein-coupled receptors (GPCRs) that are unable to bind acetylcholine (ACh), the endogenous muscarinic receptor ligand, but can be efficiently activated by clozapine-N-oxide (CNO), an otherwise pharmacologically inert compound. These CNO-sensitive designer GPCRs [alternative name: designer receptors exclusively activated by designer drug (DREADDs)] have emerged as powerful new tools to dissect the in vivo roles of distinct G protein signaling pathways in specific cell types or tissues. As is the case with other GPCRs, CNO-activated DREADDs not only couple to heterotrimeric G proteins but can also recruit proteins of the arrestin family (arrestin-2 and -3). Accumulating evidence suggests that arrestins can act as scaffolding proteins to promote signaling through G protein-independent signaling pathways. To explore the physiological relevance of these arrestin-dependent signaling pathways, the availability of an arrestin-biased DREADD would be highly desirable. In this study, we describe the development of an M3 muscarinic receptor-based DREADD [Rq(R165L)] that is no longer able to couple to G proteins but can recruit arrestins and promote extracellular signal-regulated kinase-1/2 phosphorylation in an arrestin- and CNO-dependent fashion. Moreover, CNO treatment of mouse insulinoma (MIN6) cells expressing the Rq(R165L) construct resulted in a robust, arrestin-dependent stimulation of insulin release, directly implicating arrestin signaling in the regulation of insulin secretion. This newly developed arrestin-biased DREADD represents an excellent novel tool to explore the physiological relevance of arrestin signaling pathways in distinct tissues and cell types.

Footnotes

  • This work was supported 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.

    http://dx.doi.org/10.1124/mol.112.080358.

  • ABBREVIATIONS:

    GPCR
    G protein-coupled receptor
    GRK
    G protein-coupled receptor kinases
    CNO
    clozapine-N-oxide
    DREADD
    designer receptor exclusively activated by designer drug
    MIN6
    mouse insulinoma
    ACh
    acetylcholine
    OXO-M
    oxotremorine-M
    [3H]NMS
    [3H]N-methylscopolamine
    HA
    hemagglutinin
    BRET
    bioluminescence resonance energy transfer
    Luc
    R. reniformis luciferase 8
    V-arr2
    Venus-tagged version of arrestin-2
    V-arr3
    Venus-tagged version of arrestin-3
    siRNA
    small interfering RNA
    pERK1/2
    phosphorylated ERK1/2.

  • Received May 31, 2012.
  • Accepted July 20, 2012.
  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 82 (4)
Molecular Pharmacology
Vol. 82, Issue 4
1 Oct 2012
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Rapid CommunicationAccelerated Communication

An Arrestin-Biased Designer G Protein-Coupled Receptor

Ken-ichiro Nakajima and Jürgen Wess
Molecular Pharmacology October 1, 2012, 82 (4) 575-582; DOI: https://doi.org/10.1124/mol.112.080358

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An Arrestin-Biased Designer G Protein-Coupled Receptor

Ken-ichiro Nakajima and Jürgen Wess
Molecular Pharmacology October 1, 2012, 82 (4) 575-582; DOI: https://doi.org/10.1124/mol.112.080358
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