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Methods to Study the Molecular Pharmacology of the Histamine H4 Receptor

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Book cover Histamine Receptors as Drug Targets

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

Abstract

The H4R is the latest addition of the histamine receptor family. This GPCR was found to be involved in a multitude of allergic and inflammatory diseases. Antagonizing H4Rs results in profound anti-inflammatory effects in various animal disease models, and a first phase 2a clinical trial in patients suffering from atopic dermatitis has already been conducted.

In order to accelerate and expand current drug discovery at H4R, in-depth understanding of its molecular mechanisms and signaling pathways are key. Complexity of H4R signaling pathways was highlighted by the discovery of so-called biased ligands, which can initiate differential efficacies in various GPCR responses. This chapter will provide an overview of commonly applied methods used to elucidate the molecular pharmacological aspects of the H4R from receptor-ligand-binding interactions to downstream gene transcription.

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References

  1. Panula P, Chazot PL, Cowart M et al (2015) International union of basic and clinical pharmacology. XCVIII. Histamine receptors. Pharmacol Rev 67:601–655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Arrang J-M, Garbarg M, Schwartz J-C (1983) Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature 302:832–837

    Article  CAS  PubMed  Google Scholar 

  3. Black JW, Duncan WAM, Durant CJ et al (1972) Definition and antagonism of histamine H2-receptors. Nature 236:385–390

    Article  CAS  PubMed  Google Scholar 

  4. Wells JA, Morris HC (1945) Observations on the nature of the antagonism of histamine by beta-dimethylaminoethyl benzhydryl ether (benadryl). J Pharmacol Exp Ther 85:122–128

    CAS  PubMed  Google Scholar 

  5. Liu C, Ma X, Jiang X et al (2001) Cloning and pharmacological characterization of a fourth histamine receptor (H4) expressed in bone marrow. Mol Pharmacol 59:420–426

    CAS  PubMed  Google Scholar 

  6. Oda T, Morikawa N, Saito Y et al (2000) Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes. J Biol Chem 275:36781–36786

    Article  CAS  PubMed  Google Scholar 

  7. Morse KL, Behan J, Laz TM et al (2001) Cloning and characterization of a novel human histamine receptor. J Pharmacol Exp Ther 296:1058–1066

    CAS  PubMed  Google Scholar 

  8. Zhu Y, Michalovich D, Wu H et al (2001) Cloning, expression, and pharmacological characterization of a novel human histamine receptor. Mol Pharmacol 59:434–441

    CAS  PubMed  Google Scholar 

  9. Nakamura T, Itadani H, Hidaka Y et al (2000) Molecular cloning and characterization of a new human histamine receptor, HH4R. Biochem Biophys Res Commun 279:615–620

    Article  CAS  PubMed  Google Scholar 

  10. Nguyen T, Shapiro DA, George SR et al (2001) Discovery of a novel member of the histamine receptor family. Mol Pharmacol 59:427–433

    CAS  PubMed  Google Scholar 

  11. Lim HD, Van Rijn RM, Ling P et al (2005) Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist. J Pharmacol Exp Ther 314:1310–1321

    Article  CAS  PubMed  Google Scholar 

  12. Simons FER, Simons KJ (2011) Histamine and H1-antihistamines: celebrating a century of progress. J Allergy Clin Immunol 128:1139–1150.e4

    Article  CAS  PubMed  Google Scholar 

  13. Scarpignato C (2007) New drugs to suppress acid secretion: current and future developments. Drug Discov Today Ther Strateg 4:155–163

    Article  Google Scholar 

  14. Esbenshade TA, Browman KE, Bitner RS et al (2008) The histamine H3 receptor: an attractive target for the treatment of cognitive disorders. Br J Pharmacol 154:1166–1181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dauvilliers Y, Bassetti C, Lammers GJ et al (2013) Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol 12:1068–1075

    Article  CAS  PubMed  Google Scholar 

  16. Jemima EA, Prema A, Thangam EB (2014) Functional characterization of histamine H4 receptor on human mast cells. Mol Immunol 62:19–28

    Article  CAS  PubMed  Google Scholar 

  17. Dijkstra D, Leurs R, Chazot P et al (2007) Histamine downregulates monocyte CCL2 production through the histamine H4 receptor. J Allergy Clin Immunol 120:300–307

    Article  CAS  PubMed  Google Scholar 

  18. Dijkstra D, Stark H, Chazot PL et al (2008) Human inflammatory dendritic epidermal cells express a functional histamine H4 receptor. J Invest Dermatol 128:1696–1703

    Article  CAS  PubMed  Google Scholar 

  19. Bäumer W, Wendorff S, Gutzmer R et al (2008) Histamine H4 receptors modulate dendritic cell migration through skin—immunomodulatory role of histamine. Allergy 63:1387–1394

    Article  PubMed  Google Scholar 

  20. Hofstra CL, Desai PJ, Thurmond RL (2003) Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells. J Pharmacol Exp Ther 305:1212–1221

    Article  CAS  PubMed  Google Scholar 

  21. Gantner F, Sakai K, Tusche MW et al (2002) Histamine H4 and H2 receptors control histamine-induced interleukin-16 release from human CD8(+) T cells. J Pharmacol Exp Ther 303:300–307

    Article  CAS  PubMed  Google Scholar 

  22. Novak N, Mete N, Bussmann C et al (2012) Early suppression of basophil activation during allergen-specific immunotherapy by histamine receptor 2. J Allergy Clin Immunol 130:1153–1158

    Article  CAS  PubMed  Google Scholar 

  23. Violin JD, Soergel DG, Boerrigter G et al (2013) GPCR biased ligands as novel heart failure therapeutics. Trends Cardiovasc Med 23:242–249

    Article  CAS  PubMed  Google Scholar 

  24. Kingwell K (2015) Pioneering biased ligand offers efficacy with reduced on-target toxicity. Nat Rev Drug Discov 14:809–810

    Article  CAS  PubMed  Google Scholar 

  25. Nijmeijer S, Vischer HF, Rosethorne EM et al (2012) Analysis of multiple histamine H4 receptor compound classes uncovers Gαi protein- and β-arrestin2-biased ligands. Mol Pharmacol 82:1174–1182

    Article  CAS  PubMed  Google Scholar 

  26. Nijmeijer S, Vischer HF, Sirci F et al (2013) Detailed analysis of biased histamine H4 receptor signalling by JNJ 7777120 analogues. Br J Pharmacol 170:78–88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rosethorne EM, Charlton SJ (2011) Agonist-biased signaling at the histamine H4 receptor: JNJ7777120 recruits β-arrestin without activating G proteins. Mol Pharmacol 79:749–757

    Article  CAS  PubMed  Google Scholar 

  28. Thurmond RL (2015) The histamine H4 receptor: from orphan to the clinic. Front Pharmacol 6:1–11

    Article  CAS  Google Scholar 

  29. Kollmeier A, Francke K, Chen B et al (2014) The H4 receptor antagonist, JNJ 39758979, is effective in reducing histamine-induced pruritus in a randomized clinical study in healthy subjects. J Pharmacol Exp Ther 350:181–187

    Article  PubMed  Google Scholar 

  30. Shin N, Covington M, Bian D et al (2012) INCB38579, a novel and potent histamine H4 receptor small molecule antagonist with anti-inflammatory pain and anti-pruritic functions. Eur J Pharmacol 675:47–56

    Article  CAS  PubMed  Google Scholar 

  31. Dunford PJ, O’Donnell N, Riley JP et al (2006) The histamine H4 receptor mediates allergic airway inflammation by regulating the activation of CD4(+) T cells. J Immunol 176:7062–7070

    Article  CAS  PubMed  Google Scholar 

  32. Cowden JM, Yu F, Banie H et al (2014) The histamine H4 receptor mediates inflammation and Th17 responses in preclinical models of arthritis. Ann Rheum Dis 73:600–608

    Article  PubMed  Google Scholar 

  33. Varga C, Horvath K, Berko A et al (2005) Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat. Eur J Pharmacol 522:130–138

    Article  CAS  PubMed  Google Scholar 

  34. Adami M, Pozzoli C, Menozzi A et al (2012) Effects of histamine H4 receptor ligands in a mouse model of mastric ulceration. Pharmacology 89:287–294

    Article  CAS  PubMed  Google Scholar 

  35. Murata Y, Song M, Kikuchi H et al (2015) Phase 2a, randomized, double-blind, placebo-controlled, multicenter, parallel-group study of a H4R-antagonist (JNJ-39758979) in Japanese adults with moderate atopic dermatitis. J Dermatol 42:129–139

    Article  CAS  PubMed  Google Scholar 

  36. Connelly WM, Shenton FC, Lethbridge N et al (2009) The histamine H4 receptor is functionally expressed on neurons in the mammalian CNS. Br J Pharmacol 157:55–63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Schneider EH, Seifert R (2015) The histamine H4-receptor and the central and peripheral nervous system: a critical analysis of the literature. Neuropharmacology:1–13

    Google Scholar 

  38. Altinbas B, Yilmaz MS, Savci V et al (2015) Centrally injected histamine increases posterior hypothalamic acetylcholine release in hemorrhage-hypotensive rats. Auton Neurosci 187:63–69

    Article  CAS  PubMed  Google Scholar 

  39. Feliszek M, Speckmann V, Schacht D et al (2015) A search for functional histamine H4 receptors in the human, guinea pig and mouse brain. Naunyn Schmiedebergs Arch Pharmacol 388:11–17

    Article  CAS  PubMed  Google Scholar 

  40. Lethbridge NL, Chazot PL (2010) Immunological identification of the mouse H4 histamine receptor on spinal cord motor neurons using a novel anti-mouse H4R antibody. Inflamm Res 59:S197–S198

    Article  CAS  PubMed  Google Scholar 

  41. Gutzmer R, Diestel C, Mommert S et al (2005) Histamine H4 receptor stimulation suppresses IL-12p70 production and mediates chemotaxis in human monocyte-derived dendritic cells. J Immunol 174:5224–5232

    Article  CAS  PubMed  Google Scholar 

  42. Czerner CP, Klos A, Seifert R et al (2014) Histamine induces chemotaxis and phagocytosis in murine bone marrow-derived macrophages and RAW 264.7 macrophage-like cells via histamine H4-receptor. Inflamm Res 63:239–247

    Article  CAS  PubMed  Google Scholar 

  43. Ling P, Ngo K, Nguyen S et al (2004) Histamine H4 receptor mediates eosinophil chemotaxis with cell shape change and adhesion molecule upregulation. Br J Pharmacol 142:161–171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. O’Reilly M, Alpert R, Jenkinson S et al (2002) Identification of a histamine H4 receptor on human eosinophils—role in eosinophil chemotaxis. J Recept Signal Transduct Res 22:431–448

    Article  PubMed  Google Scholar 

  45. Costa T, Cotecchia S (2005) Historical review: negative efficacy and the constitutive activity of G-protein-coupled receptors. Trends Pharmacol Sci 26:618–624

    Article  CAS  PubMed  Google Scholar 

  46. Schneider EH, Schnell D, Papa D et al (2009) High constitutive activity and a G-protein-independent high-affinity state of the human histamine H4-receptor. Biochemistry 48:1424–1438

    Article  CAS  PubMed  Google Scholar 

  47. Bakker RA, Schoonus SBJ, Smit MJ et al (2001) Histamine H1-receptor activation of nuclear factor-κB: roles for Gβγ- and Gαq/11-subunits in constitutive and agonist- mediated signaling. Mol Pharmacol 60:1133–1142

    CAS  PubMed  Google Scholar 

  48. Smit MJ, Leurs R, Alewijnse AE et al (1996) Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors. Proc Natl Acad Sci USA 93:6802–6807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Moore CAC, Milano SK, Benovic JL (2007) Regulation of receptor trafficking by GRKs and arrestins. Annu Rev Physiol 69:451–482

    Article  CAS  PubMed  Google Scholar 

  50. Marchese A, Paing MM, Temple BRS et al (2008) G protein-coupled receptor sorting to endosomes and lysosomes. Annu Rev Pharmacol Toxicol 48:601–629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Nijmeijer S, Engelhardt H, Schultes S et al (2013) Design and pharmacological characterization of VUF14480, a covalent partial agonist that interacts with cysteine 983.36 of the human histamine H4 receptor. Br J Pharmacol 170:89–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Shenoy SK, Drake MT, Nelson CD et al (2006) beta-arrestin-dependent, G protein-independent ERK1/2 activation by the beta2 adrenergic receptor. J Biol Chem 281:1261–1273

    Article  CAS  PubMed  Google Scholar 

  53. Lim HD, Smits RA, Bakker RA et al (2006) Discovery of S-(2-guanidylethyl)-isothiourea (VUF8430) as a potent nonimidazole histamine H4 receptor agonist. J Med Chem 49:6650–6651

    Article  CAS  PubMed  Google Scholar 

  54. De Lean A, Stadel JM, Lefkowitz RJ (1980) A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor. J Biol Chem 255:7108–7117

    CAS  PubMed  Google Scholar 

  55. Igel P, Schnell D, Bernhardt G et al (2009) Tritium-labeled N 1 -[3-(1 H -imidazol-4-yl)propyl]- N 2 -propionylguanidine ([ 3 H]UR-PI294), a high-affinity histamine H3 and H4 receptor radioligand. ChemMedChem 4:225–231

    Article  CAS  PubMed  Google Scholar 

  56. Nijmeijer S, Leurs R, Smit MJ et al (2010) The Epstein-Barr virus-encoded G protein-coupled receptor BILF1 hetero-oligomerizes with human CXCR4, scavenges Gαi proteins, and constitutively impairs CXCR4 functioning. J Biol Chem 285:29632–29641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hulme EC, Trevethick MA (2010) Ligand binding assays at equilibrium: validation and interpretation. Br J Pharmacol 161:1219–1237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Smits RA, Lim HD, van der Meer T et al (2012) Ligand based design of novel histamine H4 receptor antagonists; fragment optimization and analysis of binding kinetics. Bioorg Med Chem Lett 22:461–467

    Article  CAS  PubMed  Google Scholar 

  59. Harrison C, Traynor JR (2003) The [35S]GTPγS binding assay: approaches and applications in pharmacology. Life Sci 74:489–508

    Article  CAS  PubMed  Google Scholar 

  60. Bacart J, Corbel C, Jockers R et al (2008) The BRET technology and its application to screening assays. Biotechnol J 3:311–324

    Article  CAS  PubMed  Google Scholar 

  61. Salahpour A, Espinoza S, Masri B et al (2012) BRET biosensors to study GPCR biology, pharmacology, and signal transduction. Front Endocrinol 3:1–9

    Google Scholar 

  62. Barak LS, Salahpour A, Zhang X et al (2008) Pharmacological characterization of membrane-expressed human trace amine-associated receptor 1 (TAAR1) by a bioluminescence resonance energy transfer cAMP biosensor. Mol Pharmacol 74:585–594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Williams C (2004) cAMP detection methods in HTS: selecting the best from the rest. Nat Rev Drug Discov 3:125–135

    Article  CAS  PubMed  Google Scholar 

  64. Nordemann U, Wifling D, Schnell D et al (2013) Luciferase reporter gene assay on human, murine and rat histamine H4 receptor orthologs: correlations and discrepancies between distal and proximal readouts. PLoS One 8:e73961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hill SJ, Williams C, May LT (2010) Insights into GPCR pharmacology from the measurement of changes in intracellular cyclic AMP; advantages and pitfalls of differing methodologies. Br J Pharmacol 161:1266–1275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hill SJ, Baker JG, Rees S (2001) Reporter-gene systems for the study of G-protein-coupled receptors. Curr Opin Pharmacol 1:526–532

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors participated in the European COST Action BM0806. ECHO grant (711.013.014) of the Netherlands Organization of Scientific Research supported this work.

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Authors and Affiliations

  1. Faculty of Sciences, Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands

    Eléonore W. E. Verweij, Rob Leurs & Henry F. Vischer

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  1. Eléonore W. E. Verweij
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  2. Rob Leurs
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  3. Henry F. Vischer
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Correspondence to Henry F. Vischer .

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Editors and Affiliations

  1. Department of Pharmacology Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Ekaterini Tiligada

  2. Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, Northern Ireland, United Kingdom

    Madeleine Ennis

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Verweij, E.W.E., Leurs, R., Vischer, H.F. (2017). Methods to Study the Molecular Pharmacology of the Histamine H4 Receptor. In: Tiligada, E., Ennis, M. (eds) Histamine Receptors as Drug Targets. Methods in Pharmacology and Toxicology. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6843-5_6

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  • DOI: https://doi.org/10.1007/978-1-4939-6843-5_6

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-6841-1

  • Online ISBN: 978-1-4939-6843-5

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