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Molecular Pharmacology

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Research ArticlePerspective

Paradoxical Stimulatory Effects of the “Standard” Histamine H4-Receptor Antagonist JNJ7777120: the H4 Receptor Joins the Club of 7 Transmembrane Domain Receptors Exhibiting Functional Selectivity

Roland Seifert, Erich H. Schneider, Stefan Dove, Irena Brunskole, Detlef Neumann, Andrea Strasser and Armin Buschauer
Molecular Pharmacology April 2011, 79 (4) 631-638; DOI: https://doi.org/10.1124/mol.111.071266
Roland Seifert
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Erich H. Schneider
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Stefan Dove
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Irena Brunskole
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Detlef Neumann
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Andrea Strasser
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Armin Buschauer
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Abstract

The histamine H4 receptor (H4R) is expressed in several cell types of the immune system and is assumed to play an important pro-inflammatory role in various diseases, including bronchial asthma, atopic dermatitis, and pruritus. Accordingly, H4R antagonists have been suggested to provide valuable drugs for the treatment of these diseases. Over the past decade, the indole derivative 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine (JNJ7777120) has become the “standard” H4R antagonist and has been extensively used to assess the pathophysiological role of the H4R. However, the situation has now become more complicated by recent data (p. 749 and Naunyn Schmiedebergs Arch Pharmacol doi: 10.1007/s00210-011-0612-3) showing that JNJ7777120 can also activate β-arrestin in a supposedly Gi-protein-independent (pertussis toxin-insensitive) manner and that at certain H4R species orthologs, JNJ7777120 exhibits partial agonist efficacy with respect to Gi-protein activation (steady-state high-affinity GTPase activity). These novel findings can be explained within the concept of functional selectivity or biased signaling, assuming unique ligand-specific receptor conformations with distinct signal transduction capabilities. Thus, great caution must be exerted when interpreting in vivo effects of JNJ7777120 as H4R antagonism. We discuss future directions to get out of the current dilemma in which there is no “standard” H4R antagonist available to the scientific community.

Footnotes

  • This work was supported by the Deutsche Forschungsgemeinschaft [Grants GRK 760, GRK 1441, SFB 587, STR 1125/1-1] and the European Union [COST program BM0806 (H4R network)].

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

    doi:10.1124/mol.111.071266.

  • Please see the related article on page 749.

  • ABBREVIATIONS:

    GTPγS
    guanosine 5′-O-(3-thio)triphosphate
    JNJ7777120
    1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine
    7TM
    seven-transmembrane domain
    HxR
    histamine H1- H2-, H3 or H4 receptor
    c
    canine
    h
    human
    m
    mouse
    r
    rat
    PTX
    pertussis toxin
    ERK
    extracellular signal-regulated kinase
    UR-PI376
    2-cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[(2-phenylthio)ethyl]guanidine
    UR-PI294
    N1-[3-(1H-imidazol-4-yl)propyl]-N2-propionylguanidine.

  • Received January 16, 2011.
  • Accepted January 25, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (4)
Molecular Pharmacology
Vol. 79, Issue 4
1 Apr 2011
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Research ArticlePerspective

Paradoxical Stimulatory Effects of the “Standard” Histamine H4-Receptor Antagonist JNJ7777120: the H4 Receptor Joins the Club of 7 Transmembrane Domain Receptors Exhibiting Functional Selectivity

Roland Seifert, Erich H. Schneider, Stefan Dove, Irena Brunskole, Detlef Neumann, Andrea Strasser and Armin Buschauer
Molecular Pharmacology April 1, 2011, 79 (4) 631-638; DOI: https://doi.org/10.1124/mol.111.071266

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Research ArticlePerspective

Paradoxical Stimulatory Effects of the “Standard” Histamine H4-Receptor Antagonist JNJ7777120: the H4 Receptor Joins the Club of 7 Transmembrane Domain Receptors Exhibiting Functional Selectivity

Roland Seifert, Erich H. Schneider, Stefan Dove, Irena Brunskole, Detlef Neumann, Andrea Strasser and Armin Buschauer
Molecular Pharmacology April 1, 2011, 79 (4) 631-638; DOI: https://doi.org/10.1124/mol.111.071266
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  • Article
    • Abstract
    • Introduction
    • Activation of β-Arrestin by JNJ7777120: A Twisted Story
    • Even More Twists with JNJ7777120, Extending to Thioperamide
    • What Is the Molecular Basis for the Divergent Effects of JNJ7777120 on Various Signaling Pathways Promoted by hH4R? Also a Twisted Story
    • And Even More Twists: Are the Effects of JNJ7777120 on β-Arrestin Recruitment Really G-Protein-Independent?
    • Are H4R Agonists an Alternative to JNJ7777120 and Thioperamide?
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