Histamine and Its Receptors

  • Martin K. Church
Part of the Allergy Frontiers book series (ALLERGY, volume 2)

Histamine is a ubiquitous mediator in the body with numerous physiological and pathological actions. In humans, there are four subtypes of histamine receptor, H1, H2, H3 and H4, all encoded on different genes. All histamine receptors are G protein-coupled receptors (GPCRs), the superfamily of which contains at least 500 individual membrane proteins that share a common structural motif of seven-transmembrane ?-helical domains arranged in a circular fashion. Interaction of histamine with a receptor stabilizes it in its active form enabling it stimulate intracellular biochemical events. Antihistamines combine with other domains of the receptor to stabilize it in its inactive form. Thus, antihistamines are inverse agonists not receptor antagonists. Stimulation of histamine H1-receptors (Gq/11-coupled GPCRs) activates two separate intracellular biochemical cascades. The first activates phospholipase C and elevates intracellular calcium to cause the immediate effects of the allergic response, including sensory nerve stimulation, mucus production and rhinorrhoea and edema. The second, acting through protein kinase C, stimulates NF- B transcription to produce cytokines and adhesion proteins. Activation of histamine H2-receptors (Gs-coupled GPCRs), in addition to stimulating gastric acid secretion, has diverse effects on the immune system including increasing IL-10 production by dendritic cells, suppressing lymphocyte responsiveness and reducing monocytes apoptosis. Most of the effects mediated histamine H2-receptors result from the elevation of intracellular cyclic AMP levels. Stimulation of histamine H3-receptors, Gi/o-coupled GPCRs which are found almost exclusively in the brain as presynaptic receptors for histamine on nerves, decreases intracellular cyclic AMP levels to reduce neuronal function. Unlike other histamine receptors, the H4-receptor, also a Gi/o-coupled GPCR, was discovered using knowledge of the human genome and sequence information of the H3-receptor. Conclusive demonstration of which cell types express the H4-receptor has been difficult because of its low level of expression and the fact that its expression appears to be controlled by inflammatory stimuli. However, H4-receptor expression has been shown particularly on dendritic cells, eosinophils and mast cells where they are suggested to increase chemotaxis and cytokine production. This suggests that the histamine H4-receptor may represent a therapeutic target for the regulation of immune function, particularly with respect to allergy and asthma.


Mast Cell Allergy Clin Immunol Histamine Receptor Human Skin Mast Cell Human Histamine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Windaus A, Vogt W. (1907) Synthese des imidazolylathylamins. Ber Dtsch Chem Ges 3:3691–3695.CrossRefGoogle Scholar
  2. 2.
    Dale HH, Laidlaw PP. (1910) The physiological action of beta-imidazolethylamine. J Physiol 41:318–344.PubMedGoogle Scholar
  3. 3.
    Best CH, Dale HH, Dudley HW, Thorpe WV. (1927) The nature of vasodilator constituents of certain tissue extracts. J Physiol (Lond) 62:397–417.Google Scholar
  4. 4.
    Lewis T. (1927) The blood vessels of human skin and their responses. London: Shaw & Son.Google Scholar
  5. 5.
    Riley JF, West GB. (1956) Skin histamine: its location in the tissue mast cells. Arch Dermatol 74:471–478.Google Scholar
  6. 6.
    Uvnas B, Aborg C-H, Bergendorff A. (1970) Storage of histamine in mast cells. Evidence for ionic binding of histamine to protein carboxyls in the granule heparin protein complex. Acta Physiol Scand 336(Suppl):1–26.Google Scholar
  7. 7.
    Yamauchi K, Sekizawa K, Suzuki H, Nakazawa H, Ohkawara Y, Katayose D, Ohtsu H, Tamura G, Shibahara S, Takemura M. (1994) Structure and function of human histamine N-methyltransferase: critical enzyme in histamine metabolism in airway. Am J Physiol 267:L342–L349.PubMedGoogle Scholar
  8. 8.
    Okayama M, Yamauchi K, Sekizawa K, Okayama H, Sasaki H, Inamura N, Maeyama K, Watanabe T, Takishima T, Shirato K. (1995) Localization of histamine N-methyltransferase messenger RNA in human nasal mucosa. J Allergy Clin Immunol 95:96–102.PubMedCrossRefGoogle Scholar
  9. 9.
    Schomig E, Lazar A, Grundemann D. (2006) Extraneuronal monoamine transporter and organic cation transporters 1 and 2: a review of transport efficiency. Handb Exp Pharmacol 175:151–80.PubMedCrossRefGoogle Scholar
  10. 10.
    O'Sullivan S, Roquet A, Dahlen B, Dahlen S, Kumlin M. (1998) Urinary excretion of inflammatory mediators during allergen-induced early and late phase asthmatic reactions. Clin Exp Allergy 28:1332–1339.PubMedCrossRefGoogle Scholar
  11. 11.
    Maintz L, Novak N. (2007) Histamine and histamine intolerance. Am J Clin Nutr 85:1185–1196.PubMedGoogle Scholar
  12. 12.
    Schwelberger HG, Bodner E. (1997) Purification and characterization of diamine oxidase from porcine kidney and intestine. Biochim Biophys Acta 1340:152–164.PubMedGoogle Scholar
  13. 13.
    Schulman ES, Kagey-Sobotka A, MacGlashan DW, Adkinson NF, Peters SP, Schleimer RP, Lichtenstein LM. (1983) Heterogeneity of human mast cells. J Immunol 131:1936–1941.PubMedGoogle Scholar
  14. 14.
    Fox CC, Dvorak AM, Peters SP, Kagey-Sobotka A, Lichtenstein LM. (1985) Isolation and characterization of human intestinal mucosal mast cells. J Immunol 135:483–491.PubMedGoogle Scholar
  15. 15.
    Benyon RC, Lowman MA, Church MK. (1987) Human skin mast cells: their dispersion, purification and secretory characteristics. J Immunol 138:861–867.PubMedGoogle Scholar
  16. 16.
    Church MK, Bewley AP, Clough GF, Burrows LJ, Ferdinand SI, Petersen LJ. (1997) Studies into the mechanisms of dermal inflammation using cutaneous microdialysis. Int Arch Allergy Immunol 113:131–133.PubMedCrossRefGoogle Scholar
  17. 17.
    Dreskin SC, Kaliner MA, Gallin JI. (1987) Elevated urinary histamine in the hyperimmunoglobulin E and recurrent infection (Job's) syndrome: association with eczematoid dermatitis and not with infection. J Allergy Clin Immunol 79:515–522.PubMedCrossRefGoogle Scholar
  18. 18.
    Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM, Schunack W, Levi R, Haas HL. (1997) International Union of Pharmacology. XIII. Classification of histamine receptors. Pharmacol Rev 49:253–278.PubMedGoogle Scholar
  19. 19.
    Gether U. (2000) Uncovering molecular mechanisms involved in activation of G protein-coupled receptors. Endocr Rev 21:90–113.PubMedCrossRefGoogle Scholar
  20. 20.
    Leurs R, Watanabe T, Timmerman H. (2001) Histamine receptors are finally ‘coming out’. Trends Pharmacol Sci 22:337–339.CrossRefGoogle Scholar
  21. 21.
    Hill SJ. (2006) G-protein-coupled receptors: past, present and future. Br J Pharmacol 147(Suppl 1):S27–S37.PubMedCrossRefGoogle Scholar
  22. 22.
    Flower R. (2002) Drug receptors: a long engagement. Nature 415:587.PubMedCrossRefGoogle Scholar
  23. 23.
    McCudden CR, Hains MD, Kimple RJ, Siderovski DP, Willard FS. (2005) G-protein signaling: back to the future. Cell Mol Life Sci 62:551–577.PubMedCrossRefGoogle Scholar
  24. 24.
    Wieland K, Laak AM, Smit MJ, Kuhne R, Timmerman H, Leurs R. (1999) Mutational analysis of the antagonist-binding site of the histamine H(1) receptor. J Biol Chem 274:29994–30000.PubMedCrossRefGoogle Scholar
  25. 25.
    Buranda T, Waller A, Wu Y, Simons PC, Biggs S, Prossnitz ER, Sklar LA. (2007) Some Mechanistic Insights into GPCR Activation from Detergent-Solubilized Ternary Complexes on Beads. Adv Protein Chem 74:95–135.PubMedCrossRefGoogle Scholar
  26. 26.
    Ariens EJ. (1964) Molecular Pharmacology. New York: Academic.Google Scholar
  27. 27.
    Dixon RA, Kobilka BK, Strader DJ, Benovic JL, Dohlman HG, Frielle T, Bolanowski MA, Bennett CD, Rands E, Diehl RE. (1986) Cloning of the gene and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin. Nature 321:75–79.PubMedCrossRefGoogle Scholar
  28. 28.
    Leurs R, Church MK, Taglialatela M. (2002) H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects. Clin Exp Allergy 32:489–498.PubMedCrossRefGoogle Scholar
  29. 29.
    Costa T, Herz A. (1989) Antagonists with negative intrinsic activity at delta opioid receptors coupled to GTP-binding proteins. Proc Natl Acad Sci USA 86:7321–7325.PubMedCrossRefGoogle Scholar
  30. 30.
    Lefkowitz RJ, Cotecchia S, Samama P, Costa T. (1993) Constitutive activity of receptors coupled to guanine nucleotide regulatory proteins. Trends Pharmacol Sci 14:303–307.PubMedCrossRefGoogle Scholar
  31. 31.
    Bockaert J, Pin JP. (1999) Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J 18:1723–1729.PubMedCrossRefGoogle Scholar
  32. 32.
    Gilman AG. (1987) G proteins: transducers of receptor-generated signals. Annu Rev Biochem 56:615–649.PubMedCrossRefGoogle Scholar
  33. 33.
    Gillard M, Van der PC, Moguilevsky N, Massingham R, Chatelain P. (2002) Binding characteristics of cetirizine and levocetirizine to human H(1) histamine receptors: contribution of Lys(191) and Thr(194). Mol Pharmacol 61:391–399.PubMedCrossRefGoogle Scholar
  34. 34.
    Seifert R, Wenzel-Seifert K. (2002) Constitutive activity of G-protein-coupled receptors: cause of disease and common property of wild-type receptors. Naunyn Schmiedebergs Arch Pharmacol 366:381–416.PubMedCrossRefGoogle Scholar
  35. 35.
    Costa T, Cotecchia S. (2005) Historical review: Negative efficacy and the constitutive activity of G-protein-coupled receptors. Trends Pharmacol Sci 26:618–624.PubMedCrossRefGoogle Scholar
  36. 36.
    Smit MJ, Vischer HF, Bakker RA, Jongejan A, Timmerman H, Pardo L, Leurs R. (2007) Pharmacogenomic and structural analysis of constitutive g protein-coupled receptor activity. Annu Rev Pharmacol Toxicol 47:53–87.PubMedCrossRefGoogle Scholar
  37. 37.
    Koski G, Streaty RA, Klee WA. (1982) Modulation of sodium-sensitive GTPase by partial opiate agonists. An explanation for the dual requirement for Na + and GTP in inhibitory regulation of adenylate cyclase. J Biol Chem 257:14035–14040.Google Scholar
  38. 38.
    Cerione RA, Sibley DR, Codina J, Benovic JL, Winslow J, Neer EJ, Birnbaumer L, Caron MG, Lefkowitz RJ. (1984) Reconstitution of a hormone-sensitive adenylate cyclase system. The pure beta-adrenergic receptor and guanine nucleotide regulatory protein confer hormone responsiveness on the resolved catalytic unit. J Biol Chem 259:9979–9982.Google Scholar
  39. 39.
    Schipani E, Kruse K, Juppner H. (1995) A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 268:98–100.PubMedCrossRefGoogle Scholar
  40. 40.
    Pantel J, Legendre M, Cabrol S, Hilal L, Hajaji Y, Morisset S, Nivot S, Vie-Luton MP, Grouselle D, de KM, Kadiri A, Epelbaum J, Le B Y, Amselem S. (2006) Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J Clin Invest 116:760–768.PubMedCrossRefGoogle Scholar
  41. 41.
    Bakker RA, Schoonus SB, Smit MJ, Timmerman H, Leurs R. (2001) Histamine H(1)-receptor activation of nuclear factor-kappa B: roles for G beta gamma- and G alpha(q/11)-subunits in constitutive and agonist-mediated signaling. Mol Pharmacol 60:1133–1142.PubMedGoogle Scholar
  42. 42.
    Gouldson PR, Higgs C, Smith RE, Dean MK, Gkoutos GV, Reynolds CA. (2000) Dimerization and domain swapping in G-protein-coupled receptors: a computational study. Neuropsychopharmacology 23:S60–S77.PubMedCrossRefGoogle Scholar
  43. 43.
    Milligan G. (2005) Oligomerisation of G-protein-coupled receptors. J Cell Sci 114, 1265–1271.Google Scholar
  44. 44.
    van Rijn RM, Chazot PL, Shenton FC, Sansuk K, Bakker RA, Leurs R. (2006) Oligomerization of recombinant and endogenously expressed human histamine H(4) receptors. Mol Pharmacol 70:604–615.PubMedCrossRefGoogle Scholar
  45. 45.
    Agnati LF, Guidolin D, Leo G, Fuxe K. (2007) A boolean network modelling of receptor mosaics relevance of topology and cooperativity. J Neural Transm 114:77–92.PubMedCrossRefGoogle Scholar
  46. 46.
    Bakker RA, Casarosa P, Timmerman H, Smit MJ, Leurs R. (2004) Constitutively active Gq/11-coupled receptors enable signaling by co-expressed G(i/o)-coupled receptors. J Biol Chem 279:5152–5161.PubMedCrossRefGoogle Scholar
  47. 47.
    Bakker RA, Dees G, Carrillo JJ, Booth RG, Lopez-Gimenez JF, Milligan G, Strange PG, Leurs R. (2004) Domain swapping in the human histamine H1 receptor. J Pharmacol Exp Ther 311:131–138.PubMedCrossRefGoogle Scholar
  48. 48.
    Bond RA, Ijzerman AP. (2006) Recent developments in constitutive receptor activity and inverse agonism, and their potential for GPCR drug discovery. Trends Pharmacol Sci 27:92–96.PubMedCrossRefGoogle Scholar
  49. 49.
    Hancock AA. (2006) The challenge of drug discovery of a GPCR target: analysis of pre-clinical pharmacology of histamine H3 antagonists/inverse agonists. Biochem Pharmacol 71:1103–1113.PubMedCrossRefGoogle Scholar
  50. 50.
    Eglen RM, Bosse R, Reisine T. (2007) Emerging concepts of guanine nucleotide-binding protein-coupled receptor (GPCR) function and implications for high throughput screening. Assay Drug Dev Technol 5:425–451.PubMedCrossRefGoogle Scholar
  51. 51.
    Nelson CP, Challiss RA. (2007) ‘Phenotypic’ pharmacology: the influence of cellular environment on G protein-coupled receptor antagonist and inverse agonist pharmacology. Biochem Pharmacol 73:737–751.PubMedCrossRefGoogle Scholar
  52. 52.
    Scadding GK. (1999) Clinical assessment of antihistamines in rhinitis. Clin Exp Allergy 29(Suppl 3):77–81.PubMedCrossRefGoogle Scholar
  53. 53.
    Ahluwalia P, Anderson DF, Wilson SJ, McGill JI, Church MK. (2001) Nedocromil sodium and levocabastine reduce the symptoms of conjunctival allergen challenge by different mechanisms. J Allergy Clin Immunol 108:449–454.PubMedCrossRefGoogle Scholar
  54. 54.
    Bradding P, Walls AF, Holgate ST. (2006) The role of the mast cell in the pathophysiology of asthma. J Allergy Clin Immunol 117:1277–1284.PubMedCrossRefGoogle Scholar
  55. 55.
    Petersen LJ, Church MK, Skov PS. (1995) Histamine is released in the wheal but not the flare following challenge of human skin in vivo a microdialysis study. J Invest Dermatol 105:50.CrossRefGoogle Scholar
  56. 56.
    Hu Q, Deshpande S, Irani K, Ziegelstein RC. (1999) [Ca2+]i oscillation frequency regulates agonist-stimulated NF-κB transcriptional activity. J Biol Chem 274:33995–33998.PubMedCrossRefGoogle Scholar
  57. 57.
    Tanimoto A, Wang KY, Murata Y, Kimura S, Nomaguchi M, Nakata S, Tsutsui M, Sasaguri Y. (2007) Histamine upregulates the expression of inducible nitric oxide synthase in human intimal smooth muscle cells via histamine H1 receptor and NF-kappaB signaling pathway. Arterioscler Thromb Vasc Biol 27:1556–1561.PubMedCrossRefGoogle Scholar
  58. 58.
    Hart LA, Krishnan VL, Adcock IM, Barnes PJ, Chung KF. (1998) Activation and localization of transcription factor, nuclear factor-kappaB, in asthma. Am J Respir Crit Care Med 158:1585–1592.PubMedGoogle Scholar
  59. 59.
    Roth M, Black JL. (2006) Transcription factors in asthma are transcription factors a new target for asthma therapy? Curr Drug Targets 7:589–595.PubMedCrossRefGoogle Scholar
  60. 60.
    Yamamoto Y, Gaynor RB. (2001) Role of the NF-kappaB pathway in the pathogenesis of human disease states. Curr Mol Med 1:287–296.PubMedCrossRefGoogle Scholar
  61. 61.
    Arnold R, Rihoux J, Konig W. (1999) Cetirizine counter-regulates interleukin-8 release from human epithelial cells (A549). Clin Exp Allergy 29:1681–1691.PubMedCrossRefGoogle Scholar
  62. 62.
    Wu RL, Anthes JC, Kreutner W, Harris AG, West RE, Jr. (2004) Desloratadine inhibits constitutive and histamine-stimulated nuclear factor-kappaB activity consistent with inverse agonism at the histamine H1 Receptor. Int Arch Allergy Immunol 135:313–318.PubMedCrossRefGoogle Scholar
  63. 63.
    Matsubara M, Tamura T, Ohmori K, Hasegawa K. (2005) Histamine H1 receptor antagonist blocks histamine-induced proinflammatory cytokine production through inhibition of Ca2 + -dependent protein kinase C, Raf/MEK/ERK and IKK/I kappa B/NF-kappa B signal cascades. Biochem Pharmacol 69:433–449.PubMedCrossRefGoogle Scholar
  64. 64.
    Bachert C, Bousquet J, Canonica GW, Durham SR, Klimek L, Mullol J, Van Cauwenberge PB, Van HG. (2004) Levocetirizine improves quality of life and reduces costs in long-term management of persistent allergic rhinitis. J Allergy Clin Immunol 114:838–844.PubMedCrossRefGoogle Scholar
  65. 65.
    Patou J, De SH, van CP, Bachert C. (2006) Pathophysiology of nasal obstruction and meta-analysis of early and late effects of levocetirizine. Clin Exp Allergy 36:972–981.PubMedCrossRefGoogle Scholar
  66. 66.
    Canonica GW, Tarantini F, Compalati E, Penagos M. (2007) Efficacy of desloratadine in the treatment of allergic rhinitis: a meta-analysis of randomized, double-blind, controlled trials. Allergy 62:359–366.PubMedCrossRefGoogle Scholar
  67. 67.
    Church MK, Clough GF. (1999) Human skin mast cells: in vitro and in vivo studies. Ann Allergy Asthma Immunol 83:471–475.PubMedCrossRefGoogle Scholar
  68. 68.
    Cohan VL, MacGlashan DW, Jr., Warner JA, Lichtenstein LM, Proud D. (1991) Mechanisms of mediator release from human skin mast cells upon stimulation by the bradykinin analog, [DArg0-Hyp3-DPhe7]bradykinin. Biochem Pharmacol 41:293–300.PubMedCrossRefGoogle Scholar
  69. 69.
    Wallengren J, Hakanson R. (1992) Effects of capsaicin, bradykinin and prostaglandin E2 in the human skin. Br J Dermatol 126:111–117.PubMedCrossRefGoogle Scholar
  70. 70.
    Li Kam Wa TC, Cooke ED, Turner P. (1992) Effects of selective histamine receptor antagonists on skin responses to intradermal bradykinin in healthy volunteers. J Pharm Pharmacol 44:869–872.Google Scholar
  71. 71.
    Sansom JE, Brooks J, Burton JL, Archer CB. (1996) Effects of H1- and H2-antihistamines on platelet-activating factor and bradykinin-induced inflammatory responses in human skin. Clin Exp Dermatol 21:33–37.PubMedCrossRefGoogle Scholar
  72. 72.
    Clough GF, Bennett AR, Church MK. (1998) Effects of H1 antagonists on the cutaneous vascular response to histamine and bradykinin: a study using scanning laser Doppler imaging. Br J Dermatol 138:806–814.PubMedCrossRefGoogle Scholar
  73. 73.
    Fadel R, Ramboer I, Chatterjee N, Rihoux JP, Derde MP. (2000) Cetirizine inhibits bradykinin-induced cutaneous wheal and flare in atopic and healthy subjects. Allergy 55:382–385.PubMedCrossRefGoogle Scholar
  74. 74.
    Fadel R, Herpin-Richard N, Rihoux JP, Henocq E. (1987) Inhibitory effect of cetirizine 2HCl on eosinophil migration in vivo. Clin Allergy 17:373–379.PubMedCrossRefGoogle Scholar
  75. 75.
    Petersen LJ, Skov PS. (1995) Methacholine induces wheal-and-flare reactions in human skin but does not release histamine in vivo as assessed by the skin microdialysis technique. Allergy 50:976–980.PubMedCrossRefGoogle Scholar
  76. 76.
    Petersen LJ, Church MK, Skov PS. (1997) Platelet-activating factor induces histamine release from human skin mast cells in vivo, which is reduced by local nerve blockade. J Allergy Clin Immunol 99:640–647.PubMedCrossRefGoogle Scholar
  77. 77.
    Chung KF, Minette P, McCusker M, Barnes PJ. (1988) Ketotifen inhibits the cutaneous but not the airway responses to platelet-activating factor in man. J Allergy Clin Immunol 81:1192–1198.PubMedCrossRefGoogle Scholar
  78. 78.
    Rajakulasingam K, Polosa R, Lau LC, Church MK, Holgate ST, Howarth PH. (1992) The influence of terfenadine and ipratropium bromide alone and in combination on bradykinin-induced nasal symptoms and plasma protein leakage. Clin Exp Allergy 22:717–723.PubMedCrossRefGoogle Scholar
  79. 79.
    Polosa R, Phillips GD, Lai CK, Holgate ST. (1990) Contribution of histamine and prostanoids to bronchoconstriction provoked by inhaled bradykinin in atopic asthma. Allergy 45:174–182.PubMedCrossRefGoogle Scholar
  80. 80.
    Erdos EG, Jackman HL, Brovkovych V, Tan F, Deddish PA. (2002) Products of angiotensin I hydrolysis by human cardiac enzymes potentiate bradykinin. J Mol Cell Cardiol 34:1569–1576.PubMedCrossRefGoogle Scholar
  81. 81.
    Monti JM. (1993) Involvement of histamine in the control of the waking state. Life Sci 53:1331–1338.PubMedCrossRefGoogle Scholar
  82. 82.
    Yamashita M, Fukui H, Sugama K, Horio Y, Ito S, Mizuguchi H, Wada H. (1991) Expression cloning of a cDNA encoding the bovine histamine H1 receptor. Proc Natl Acad Sci USA 88:11515–11519.PubMedCrossRefGoogle Scholar
  83. 83.
    Fujimoto K, Horio Y, Sugama K, Ito S, Liu YQ, Fukui H. (1993) Genomic cloning of the rat histamine H1 receptor. Biochem Biophys Res Commun 190:294–301.PubMedCrossRefGoogle Scholar
  84. 84.
    Horio Y, Mori Y, Higuchi I, Fujimoto K, Ito S, Fukui H. (1993) Molecular cloning of the guinea-pig histamine H1 receptor gene. J Biochem (Tokyo) 114:408–414.Google Scholar
  85. 85.
    Fukui H, Fujimoto K, Mizuguchi H, Sakamoto K, Horio Y, Takai S, Yamada K, Ito S. (1994) Molecular cloning of the human histamine H1 receptor gene. Biochem Biophys Res Commun 201:894–901.PubMedCrossRefGoogle Scholar
  86. 86.
    Le Coniat M, Traiffort E, Ruat M, Arrang JM, Berger R. (1994) Chromosomal localization of the human histamine H1-receptor gene. Hum Genet 94:186–188.PubMedCrossRefGoogle Scholar
  87. 87.
    De Backer MD, Gommeren W, Moereels H, Nobels G, Van GP, Leysen JE, Luyten WH. (1993) Genomic cloning, heterologous expression and pharmacological characterization of a human histamine H1 receptor. Biochem Biophys Res Commun 197:1601–1608.PubMedCrossRefGoogle Scholar
  88. 88.
    Leurs R, Go JN, Bast A, Timmerman H. (1989) Involvement of protein kinase C in the histamine H1-receptor mediated contraction of guinea-pig lung parenchymal strips. Agents Actions 27:180–183.PubMedCrossRefGoogle Scholar
  89. 89.
    Exton JH. (1997) Cell signalling through guanine-nucleotide-binding regulatory proteins (G proteins) and phospholipases. Eur J Biochem 243:10–20.PubMedCrossRefGoogle Scholar
  90. 90.
    Black JW, Duncan WA, Durant CJ, Ganellin CR, Parsons EM. (1972) Definition and antagonism of histamine H2-receptors. Nature 236:385–390.PubMedCrossRefGoogle Scholar
  91. 91.
    Del Valle J, Gantz I. (1997) Novel insights into histamine H2 receptor biology. Am J Physiol 273:G987–G996.PubMedGoogle Scholar
  92. 92.
    Jutel M, Watanabe T, Klunker S, Akdis M, Thomet OA, Malolepszy J, Zak-Nejmark T, Koga R, Kobayashi T, Blaser K, Akdis CA. (2001) Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature 413:420–425.PubMedCrossRefGoogle Scholar
  93. 93.
    Akdis CA, Blaser K. (2003) Histamine in the immune regulation of allergic inflammation. J Allergy Clin Immunol 112:15–22.PubMedCrossRefGoogle Scholar
  94. 94.
    Muller U, Hari Y, Berchtold E. (2001) Premedication with antihistamines may enhance efficacy of specific-allergen immunotherapy. J Allergy Clin Immunol 107:81–86.PubMedCrossRefGoogle Scholar
  95. 95.
    Jutel M, Akdis CA. (2007) Histamine as an immune modulator in chronic inflammatory responses. Clin Exp Allergy 37:308–310.PubMedCrossRefGoogle Scholar
  96. 96.
    Soga F, Katoh N, Kishimoto S. (2007) Histamine prevents apoptosis in human monocytes. Clin Exp Allergy 37:323–330.PubMedCrossRefGoogle Scholar
  97. 97.
    Gantz I, Schaffer M, DelValle J, Logsdon C, Campbell V, Uhler M, Yamada T. (1991) Molecular cloning of a gene encoding the histamine H2 receptor. Proc Natl Acad Sci USA 88:429–433.PubMedCrossRefGoogle Scholar
  98. 98.
    Wenzel-Seifert K, Kelley MT, Buschauer A, Seifert R. (2001) Similar apparent constitutive activity of human histamine H(2)-receptor fused to long and short splice variants of G(salpha). J Pharmacol Exp Ther 299:1013–1020.PubMedGoogle Scholar
  99. 99.
    Wang L, Gantz I, DelValle J. (1996) Histamine H2 receptor activates adenylate cyclase and PLC via separate GTP-dependent pathways. Am J Physiol 271:G613–G620.PubMedGoogle Scholar
  100. 100.
    Wang LD, Hoeltzel M, Gantz I, Hunter R, Del VJ. (1998) Characterization of the histamine H2 receptor structural components involved in dual signaling. J Pharmacol Exp Ther 285:573–578.PubMedGoogle Scholar
  101. 101.
    Wellner-Kienitz MC, Bender K, Meyer T, Pott L. (2003) Coupling to Gs and G(q/11) of histamine H2 receptors heterologously expressed in adult rat atrial myocytes. Biochim Biophys Acta 1642:67–77.PubMedCrossRefGoogle Scholar
  102. 102.
    Arrang JM, Garbarg M, Schwartz JC. (1983) Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature 302:832–837.PubMedCrossRefGoogle Scholar
  103. 103.
    Arrang JM, Garbarg M, Lancelot JC, Lecomte JM, Pollard H, Robba M, Schunack W, Schwartz JC. (1987) Highly potent and selective ligands for histamine H3-receptors. Nature 327:117–123.PubMedCrossRefGoogle Scholar
  104. 104.
    Lovenberg TW, Roland BL, Wilson SJ, Jiang X, Pyati J, Huvar A, Jackson MR, Erlander MG. (1999) Cloning and functional expression of the human histamine H3 receptor. Mol Pharmacol 55:1101–1107.PubMedGoogle Scholar
  105. 105.
    Martinez-Mir MI, Pollard H, Moreau J, Arrang JM, Ruat M, Traiffort E, Schwartz JC, Palacios JM. (1990) Three histamine receptors (H1, H2 and H3) visualized in the brain of human and non-human primates. Brain Res 526:322–327.PubMedCrossRefGoogle Scholar
  106. 106.
    Wijtmans M, Leurs R, de Esch I. (2007) Histamine H3 receptor ligands break ground in a remarkable plethora of therapeutic areas. Expert Opin Investig Drugs 16:967–985.PubMedCrossRefGoogle Scholar
  107. 107.
    Celanire S, Wijtmans M, Talaga P, Leurs R, de Esch I. (2005) Keynote review: histamine H3 receptor antagonists reach out for the clinic. Drug Discov Today 10:1613–27.PubMedCrossRefGoogle Scholar
  108. 108.
    Leurs R, Bakker RA, Timmerman H, de Esch I. (2005) The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat Rev Drug Discov 4:107–120.PubMedCrossRefGoogle Scholar
  109. 109.
    Coge F, Guenin SP, Audinot V, Renouard-Try A, Beauverger P, Macia C, Ouvry C, Nagel N, Rique H, Boutin JA, Galizzi JP. (2001) Genomic organization and characterization of splice variants of the human histamine H3 receptor. Biochem J 355:279–288.PubMedCrossRefGoogle Scholar
  110. 110.
    Lim HD, Smits RA, Leurs R, de Esch I. (2006) The emerging role of the histamine H4 receptor in anti-inflammatory therapy. Curr Top Med Chem 6:1365–1373.PubMedGoogle Scholar
  111. 111.
    Bongers G, Bakker RA, Leurs R. (2007) Molecular aspects of the histamine H3 receptor. Biochem Pharmacol 73:1195–1204.PubMedCrossRefGoogle Scholar
  112. 112.
    Wellendorph P, Goodman MW, Burstein ES, Nash NR, Brann MR, Weiner DM. (2002) Molecular cloning and pharmacology of functionally distinct isoforms of the human histamine H(3) receptor. Neuropharmacology 42:929–940.PubMedCrossRefGoogle Scholar
  113. 113.
    Burgaud JL, Oudart N. (1993) Bronchodilatation of guinea-pig perfused bronchioles induced by the H3-receptor for histamine: role of epithelium. Br J Pharmacol 109:960–966.PubMedGoogle Scholar
  114. 114.
    Thiels E, Klann E. (2001) Extracellular signal-regulated kinase, synaptic plasticity, and memory. Rev Neurosci 12:327–345.PubMedGoogle Scholar
  115. 115.
    Silver RB, Poonwasi KS, Seyedi N, Wilson SJ, Lovenberg TW, Levi R. (2002) Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings. Proc Natl Acad Sci USA 99:501–506.PubMedCrossRefGoogle Scholar
  116. 116.
    Silver RB, Mackins CJ, Smith NC, Koritchneva IL, Lefkowitz K, Lovenberg TW, Levi R. (2001) Coupling of histamine H3 receptors to neuronal Na + /H + exchange: a novel protective mechanism in myocardial ischemia. Proc Natl Acad Sci USA 98: 2855–2859.PubMedCrossRefGoogle Scholar
  117. 117.
    Oda T, Morikawa N, Saito Y, Masuho Y, Matsumoto S. (2000) Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes. J Biol Chem 275:36781–36786.PubMedCrossRefGoogle Scholar
  118. 118.
    Nakamura T, Itadani H, Hidaka Y, Ohta M, Tanaka K. (2000) Molecular cloning and characterization of a new human histamine receptor, HH4R. Biochem Biophys Res Commun 279:615–620.PubMedCrossRefGoogle Scholar
  119. 119.
    Coge F, Guenin SP, Rique H, Boutin JA, Galizzi JP. (2001) Structure and expression of the human histamine H4-receptor gene. Biochem Biophys Res Commun 284:301–309.PubMedCrossRefGoogle Scholar
  120. 120.
    Liu C, Wilson SJ, Kuei C, Lovenberg TW. (2001) Comparison of human, mouse, rat, and guinea pig histamine H4 receptors reveals substantial pharmacological species variation. J Pharmacol Exp Ther 299:121–130.PubMedGoogle Scholar
  121. 121.
    Hofstra CL, Desai PJ, Thurmond RL, Fung-Leung WP. (2003) Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells. J Pharmacol Exp Ther 305:1212–1221.PubMedCrossRefGoogle Scholar
  122. 122.
    Lippert U, Artuc M, Grutzkau A, Babina M, Guhl S, Haase I, Blaschke V, Zachmann K, Knosalla M, Middel P, Kruger-Krasagakis S, Henz BM. (2004) Human skin mast cells express H2 and H4, but not H3 receptors. J Invest Dermatol 123:116–123.PubMedCrossRefGoogle Scholar
  123. 123.
    Nguyen T, Shapiro DA, George SR, Setola V, Lee DK, Cheng R, Rauser L, Lee SP, Lynch KR, Roth BL, O'Dowd BF. (2001) Discovery of a novel member of the histamine receptor family. Mol Pharmacol 59:427–433.PubMedGoogle Scholar
  124. 124.
    O'Reilly M, Alpert R, Jenkinson S, Gladue RP, Foo S, Trim S, Peter B, Trevethick M, Fidock M. (2002) Identification of a histamine H4 receptor on human eosinophils — role in eosinophil chemotaxis. J Recept Signal Transduct Res 22:431–448.PubMedCrossRefGoogle Scholar
  125. 125.
    Buckland KF, Williams TJ, Conroy DM. (2003) Histamine induces cytoskeletal changes in human eosinophils via the H(4) receptor. Br J Pharmacol 140:1117–1127.PubMedCrossRefGoogle Scholar
  126. 126.
    Ling P, Ngo K, Nguyen S, Thurmond RL, Edwards JP, Karlsson L, Fung-Leung WP. (2004) Histamine H4 receptor mediates eosinophil chemotaxis with cell shape change and adhesion molecule upregulation. Br J Pharmacol 142:161–171.PubMedCrossRefGoogle Scholar
  127. 127.
    Takeshita K, Sakai K, Bacon KB, Gantner F. (2003) Critical role of histamine H4 receptor in leukotriene B4 production and mast cell-dependent neutrophil recruitment induced by zymosan in vivo. J Pharmacol Exp Ther 307:1072–1078.PubMedCrossRefGoogle Scholar
  128. 128.
    Dunford PJ, O'Donnell N, Riley JP, Williams KN, Karlsson L, Thurmond RL. (2006) The histamine H4 receptor mediates allergic airway inflammation by regulating the activation of CD4 + T cells. J Immunol 176:7062–7070.PubMedGoogle Scholar
  129. 129.
    Ikawa Y, Suzuki M, Shiono S, Ohki E, Moriya H, Negishi E, Ueno K. (2005) Histamine H4 receptor expression in human synovial cells obtained from patients suffering from rheumatoid arthritis. Biol Pharm Bull 28:2016–2018.PubMedCrossRefGoogle Scholar
  130. 130.
    Grzybowska-Kowalczyk A, Wojtecka-Lukasik E, Maslinska D, Gujski M, Maslinski S. (2007) Distribution pattern of histamine H4 receptor in human synovial tissue from patients with rheumatoid arthritis. Inflamm Res 56(Suppl 1):S59–S60.PubMedCrossRefGoogle Scholar
  131. 131.
    Fogel WA, Lewinski A, Jochem J. (2005) Histamine in idiopathic inflammatory bowel diseases–not a standby player. Folia Med Cracov 46:107–118.PubMedGoogle Scholar
  132. 132.
    Jokuti A, Hellinger E, Hellinger A, Darvas Z, Falus A, Thurmond RL, Hirschberg A. (2007) Histamine H4 receptor expression is elevated in human nasal polyp tissue. Cell Biol Int 31:1367–1370.PubMedCrossRefGoogle Scholar
  133. 133.
    Szewczyk G, Maslinska D, Szukiewicz D, Smiertka W, Klimkiewicz J, Pyzlak M. (2007) Histamine H4 receptors in human placenta in diabetes-complicated pregnancy. Inflamm Res 56(Suppl 1):S31–S32.PubMedCrossRefGoogle Scholar
  134. 134.
    Zhu Y, Michalovich D, Wu H, Tan KB, Dytko GM, Mannan IJ, Boyce R, Alston J, Tierney LA, Li X, Herrity NC, Vawter L, Sarau HM, Ames RS, Davenport CM, Hieble JP, Wilson S, Bergsma DJ, Fitzgerald LR. (2001) Cloning, expression, and pharmacological characterization of a novel human histamine receptor. Mol Pharmacol 59:434–441.PubMedGoogle Scholar
  135. 135.
    de Esch I, Thurmond RL, Jongejan A, Leurs R. (2005) The histamine H4 receptor as a new therapeutic target for inflammation. Trends Pharmacol Sci 26:462–469.PubMedGoogle Scholar
  136. 136.
    Yates SL, Gallagher MJ. (2007) Histamine receptor H4 polynucleotides. Merck & Co. Inc. 10488421 [US Patent 7164003].Google Scholar
  137. 137.
    Morse KL, Behan J, Laz TM, West RE, Jr., Greenfeder SA, Anthes JC, Umland S, Wan Y, Hipkin RW, Gonsiorek W, Shin N, Gustafson EL, Qiao X, Wang S, Hedrick JA, Greene J, Bayne M, Monsma FJ, Jr. (2001) Cloning and characterization of a novel human histamine receptor. J Pharmacol Exp Ther 296:1058–1066.PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Martin K. Church
    • 1
  1. 1.Infection, Inflammation and Repair Research Division, South Block 825Southampton General HospitalSouthamptonUK

Personalised recommendations