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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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  • Authors' Response to R.L. Thurmond
    Roland Seifert
    Published on: 31 May 2011
  • Response to Seifert et al.
    Robin L. Thurmond
    Published on: 31 May 2011
  • Published on: (31 May 2011)
    Page navigation anchor for Authors' Response to R.L. Thurmond
    Authors' Response to R.L. Thurmond
    • Roland Seifert

    We would like to thank Dr. Thurmond for his valuable and thoughtful comments on our "Perspective" article discussing newly discovered paradoxical effects of JNJ7777120, the most widely used H4-receptor antagonist. Dr. Thurmond correctly points out that in light of the emerging concept of functional selectivity of GPCRs, it is mandatory not to rely on a single pharmacological tool but rather to analyze carefully and in a...

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    We would like to thank Dr. Thurmond for his valuable and thoughtful comments on our "Perspective" article discussing newly discovered paradoxical effects of JNJ7777120, the most widely used H4-receptor antagonist. Dr. Thurmond correctly points out that in light of the emerging concept of functional selectivity of GPCRs, it is mandatory not to rely on a single pharmacological tool but rather to analyze carefully and in an unbiased manner an array of structurally distinct ligands. Moreover, the gene knock-out animals should be analyzed to exclude effects not related to the specific GPCR being analyzed. This approach extends beyond the H4-receptor and should be applied to any given GPCR, being a principle of general pharmacological relevance.

    Dr. Thurmond cites several studies in which the inhibitory pharmacological effects of JNJ7777120 were found to be in parallel with the phenotypes observed in the H4-receptor knock-out mice. We fully concur with the conclusion that these studies support the notion that in these systems, JNJ7777120 does act as an H4-receptor antagonist.

    We also agree with Dr. Thurmond that to this end, the number of studies reporting on paradoxical effects of JNJ7777120 is very limited and that these studies were conducted with recombinant ("artifical") systems. Thus, conclusions about functional selectivity of JNJ7777120 are restricted to such systems until now. To this end, we know only very little about the factors that may have an impact on functional selectivity of H4-receptor ligands. Those factors may include receptor species orthologs, receptor dimerization, receptor density, gylcosylation, the presence of specific G-protein heterotrimers, RGS-proteins and arrestins, compartmentation of signalling proteins and lipid composition of the membrane, to name a few factors. It is also possible that long-term exposure of cells/animals to JNJ7777120 yields very different effects than short-term exposure, and this could be due to differential blockade/activation of signalling pathways. Along the same line, simultaneous stimulatory and inhibitory effects of JNJ7777120 could cancel out each other. As stated by Dr. Thurmond, it is very important to watch out for potential functional selectivity of JNJ7777120 in native cells that express signalling proteins at physiologically relevant concentrations.

    The purpose of our perspective was to discuss the very interesting pharmacological effects of JNJ7777120 that shed light on the mechanisms of H4-receptor function in particular and GPCR function in general. Moreover, the paradoxical effects of JNJ7777120 may yield drugs that show specific effects in a disease without exhibiting unwanted effects. Most importantly, as “take-home message�, we wished to alert researchers that it is wise to look at JNJ7777120 in a very open-minded and unbiased manner and not to ignore unexpected and paradoxical ligand effects. Simplicistic assumptions about H4-receptor function and pharmacology may already have introduced a publication bias, i.e. researchers may have observed effects of JNJ7777120 that "do not fit", but have elected not to follow up these effects and left them unpublished in order to avoid "trouble" in the peer review process. Therefore, we strongly encourage the scientific community to follow up on "non-fitting" observations on JNJ7777120 and other H4-receptor ligands. In the long run, such a strategy will result in a better understanding of the H4-receptor and drugs that target this receptor although in the short run, the review process may become more difficult.

    In conclusion, we concur with Dr. Thurmond that a number of carefully conducted studies support the notion that in the systems analyzed JNJ7777120 acts as H4-receptor antagonist and that clear-cut interpretations can be obtained, specifically if control experiments with other H4-receptor antagonists and knock-out mice are properly performed. However, we have to watch out very carefully for the unexpected and need to report the unexpected to the scientific community in peer-reviewed publications to advance the field.

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    Competing Interests: None declared.
  • Published on: (31 May 2011)
    Page navigation anchor for Response to Seifert et al.
    Response to Seifert et al.
    • Robin L. Thurmond

    The commentary by Seifert et al. (Seifert et al., 2011) provides a very important discussion on the pharmacology of the histamine H4 receptor (H4R) and summarizes recent work indicating that our understanding of the receptor is incomplete. Most importantly it has been shown that the receptor, as for many GPCRs, can exhibit functional selectivity (Kenakin, 2011; Rosethorne and Charlton, 2011). This is a very important poin...

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    The commentary by Seifert et al. (Seifert et al., 2011) provides a very important discussion on the pharmacology of the histamine H4 receptor (H4R) and summarizes recent work indicating that our understanding of the receptor is incomplete. Most importantly it has been shown that the receptor, as for many GPCRs, can exhibit functional selectivity (Kenakin, 2011; Rosethorne and Charlton, 2011). This is a very important point with regard to applying pharmacological tools to understand receptor function. Indeed it underscores a very important principle that is largely ignored – data from a single ligand should never be used to make overall conclusions about the function of the receptor it targets. The reason for this is that despite our best efforts it is almost impossible to completely understand the pharmacology of any ligand and how it may differ in different species, cell types or conditions. Because of these factors, researchers must use a combination of tools including agonist/antagonist pairs, ligands of from different chemical classes, and/or knock-out animals before making conclusions about the function of receptor. The use of a single ligand only gives firm conclusions about the action of that ligand under the given experimental conditions.

    However, Seifert et al. overstate the case concerning the H4R tool compound, JNJ 7777120. JNJ 7777120 was described as a potent and selective antagonist of the H4R receptor and has been widely adopted as the standard antagonist in the field. However as Seifert et al. summarize, recent data in artificial transfected systems has uncovered other pharmacology of the ligand at the receptor besides antagonism including functional selectivity and even agonism. This led Seifert et al. to suggest that many of the activities attributed to H4R antagonism by JNJ 7777120 may in fact be something else. However, while these other pharmacological effects may exist, most of the current data support the fact that JNJ 7777120 is an antagonist in vivo and in primary cells. Perhaps one of the best examples of this is in the role of the receptor in mediating pruritic responses in mice. Dunford et al. (Dunford et al., 2007) reported that histamine- induced scratching in mice could be blocked by JNJ 77777120 and did not occur in H4R-deficient mice. Furthermore, other H4R agonists also induce scratching that can be blocked by JNJ 7777120, but cannot induce scratching in H4R-deficient mice (Dunford et al., 2007; Yu et al., 2010). Other antagonists also block this response (Cowart et al., 2008; Koenig et al., 2010). The data then clearly support the role on JNJ 77777120 as an antagonist for this effect. The compound reverses the effect of agonists and mimics the findings in animal lacking the H4R. However, this cannot be generalized. For example JNJ 7777120 also has been shown to block substance P induced itch (Yamaura et al., 2009). While is it appropriate to speculate that H4R activation is involved in substance P induced itch based on data in other models, it would take studies in H4R-deficeint mice or with other structurally distinct antagonist to firmly conclude this.

    Similar conclusions arise when looking at the effects on JNJ 7777120 in models of asthma and dermatitis, where the results are consistent between JNJ 77777120, other structurally distinct ligands and H4R- deficient mice (Cowden et al., 2010; Dunford et al., 2006). Despite of this Seifert et al. use the mouse asthma data as an example of how it is difficult to interpret the pharmacology of the H4R. Once again the data do not completely support this. JNJ 7777120 shows anti-inflammatory activities in mouse models of asthma that are mimicked by H4R-deficeint mice (Dunford et al., 2006). Furthermore, other described H4R antagonists show the same effects (Afton et al., 2010; Dunford et al., 2006). The only confusing data is that of Morgan et al. (Morgan et al., 2007) that shows that an inhaled H4R agonist, 4-methylhistamine, is anti-inflammatory. This more likely reflects differences in systemic versus local delivery or the fact that 4-methylhistamine is also an H2R agonist as pointed out by Seifert et al. rather than supporting the conclusion that H4R agonism is anti-inflammatory.

    Some of the in vivo data also yield insight as to the role of functional selectivity at the H4R. In the models of pruritus, asthma and dermatitis the phenotype is the same between JNJ 7777120-treated and H4R- deficient mice (Cowden et al., 2010; Dunford et al., 2006; Dunford et al., 2007). This suggests that in if the induction of beta-arrestin shown by Rosethorne and Charlton occurs in mice, it has little impact on the activity of the compound in these models. If JNJ 7777120-induced arrestin pathways are anti-inflammatory then they would not exist in the receptor deficient animals. Once again the most likely explanation is that the compound functions as an antagonist of the receptor. This does not mean, however, that the possibility of functional selectivity should be dismissed and it may suggest that not all antagonists are created equal if they block only a subset of the receptor pathways.

    In conclusion, although in some reporter systems JNJ 7777120 can act as an agonist or exhibit functional selectivity, the bulk of the current data in vivo and in primary cell lines indicate that it functions as an antagonist and that the anti-inflammatory, anti-nociceptive and anti- pruritic activities exhibited by JNJ 77777120 are clearly due to antagonism of the H4R. This does not mean that the one should ignore the findings of Seifert et al. and Rosethorne and Charlton, indeed the opposite is true, however these findings need to be confirmed in primary cell systems. As with any receptor system findings with a single ligand, including JNJ 7777120, should be validated with receptor-deficient animals or with a structurally distinct compounds before conclusions about receptor function can be made. Therefore, while I agree with the statement by Seifert et al. that “…great caution must be exerted when interpreting effects of JNJ7777120 as H4R antagonism�, the current data clearly do not support their conclusion that there is no “standard� H4R antagonist available.

    Afton J, Sanchez-Gomez S, Fernandez A, Gil-Torregrosa B, Ardanaz N, Gomez-Valades G, Mascaro C, Carceller E, Gomez L, Balso D, Bartroli J and Merlos M (2010) UR-63325, a novel H4 receptor antagonist that shows good efficacy in an ovalbumin-induced mouse asthma model. EAACI 2010 Meeting London:poster.

    Cowart MD, Altenbach RJ, Liu H, Hsieh GC, Drizin I, Milicic I, Miller TR, Witte DG, Wishart N, Fix-Stenzel SR, McPherson MJ, Adair RM, Wetter JM, Bettencourt BM, Marsh KC, Sullivan JP, Honore P, Esbenshade TA and Brioni JD (2008) Rotationally Constrained 2,4-Diamino-5,6-disubstituted Pyrimidines: A New Class of Histamine H4 Receptor Antagonists with Improved Druglikeness and in Vivo Efficacy in Pain and Inflammation Models. J Med Chem 51(20):6547-6557.

    Cowden JM, Zhang M, Dunford PJ and Thurmond RL (2010) The Histamine H4 Receptor Mediates Inflammation and Pruritus in Th2-Dependent Dermal Inflammation. J Invest Dermatol 130:1023-1033.

    Dunford PJ, O'Donnell N, Riley JP, Williams KN, Karlsson L and Thurmond RL (2006) The histamine H4 receptor mediates allergic airway inflammation by regulating the activation of CD4+ T cells. J Immunol 176(11):7062-7070.

    Dunford PJ, Williams KN, Desai PJ, Karlsson L, McQueen D and Thurmond RL (2007) Histamine H4 receptor antagonists are superior to traditional antihistamines in the attenuation of experimental pruritus. J Allergy Clin Immunol 119(1):176-183.

    Kenakin T (2011) Functional selectivity and biased receptor signaling. J Pharmacol Exp Ther 336(2):296-302.

    Koenig JR, Liu H, Drizin I, Witte DG, Carr TL, Manelli AM, Milicic I, Strakhova MI, Miller TR, Esbenshade TA, Brioni JD and Cowart M (2010) Rigidified 2-aminopyrimidines as histamine H4 receptor antagonists: Effects of substitution about the rigidifying ring. Bioorg Med Chem Lett 20(6):1900-1904.

    Morgan RK, McAllister B, Cross L, Green DS, Kornfeld H, Center DM and Cruikshank WW (2007) Histamine 4 receptor activation induces recruitment of FoxP3+ T cells and inhibits allergic asthma in a murine model. J Immunol 178(12):8081-8089.

    Rosethorne EM and Charlton SJ (2011) Agonist-biased signalling at the histamine H4 receptor: JNJ7777120 recruits beta-arrestin without activating G proteins. Mol Pharmacol.

    Seifert R, Schneider EH, Dove S, Brunskole I, Neumann D, Strasser A and Buschauer A (2011) Paradoxical stimulatory effects of the "standard" histamine H4-receptor antagonist JNJ7777120: The H4-receptor joins the club of 7TM receptors exhibiting functional selectivity. Mol Pharmacol in press.

    Yamaura K, Oda M, Suwa E, Suzuki M, Sato H and Ueno K (2009) Expression of histamine H4 receptor in human epidermal tissues and attenuation of experimental pruritus using H4 receptor antagonist. J Toxicol Sci 34(4):427-431.

    Yu F, Wolin RL, Wei J, Desai PJ, McGovern PM, Dunford PJ, Karlsson L and Thurmond RL (2010) Pharmacological characterization of oxime agonists of the histamine H4 receptor. Journal of Receptor, Ligand and Channel Research 3:37-49.

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    Competing Interests: None declared.
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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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