Histamine H4 receptor explained

The histamine H4 receptor, like the other three histamine receptors, is a member of the G protein-coupled receptor superfamily that in humans is encoded by the HRH4 gene.[1] [2] [3]

Discovery

Unlike the histamine receptors discovered earlier, H4 was found in 2000 through a search of the human genomic DNA data base.[4]

Tissue distribution

H4 is highly expressed in bone marrow and white blood cells and regulates neutrophil release from bone marrow and subsequent infiltration in the zymosan-induced pleurisy mouse model.[5] It was also found that H4 receptor exhibits a uniform expression pattern in the human oral epithelium.[6]

Function

The Histamine H4 receptor has been shown to be involved in mediating eosinophil shape change and mast cell chemotaxis.[7] This occurs via the βγ subunit acting at phospholipase C to cause actin polymerization and eventually chemotaxis.[7]

The histamine H4 receptor has been identified as a vital regulator of the immune system, involved in eosinophil migration, mast cell recruitment, dendritic cell activation, and T cell differentiation. The discovery of this receptor has brought it to increasing attention for its therapeutic use in inflammatory diseases such as allergy, asthma, chronic itch, and autoimmune diseases.

Structure

The 3D structure of the H4 receptor has not been solved yet due to the difficulties of GPCR crystallization. Some attempts have been made to develop structural models of the H4 receptor for different purposes. The first H4 receptor model[8] was built by homology modelling based on the crystal structure of bovine rhodopsin.[9] This model was used for the interpretation of site-directed mutagenesis data, which revealed the crucial importance of Asp94 (3.32) and Glu182 (5.46) residues in ligand binding and receptor activation.

A second rhodopsin based structural model of the H4 receptor was successfully used for the identification of novel H4 ligands.[10]

Recent advancements in GPCR crystallization, in particular the determination of the human histamine H1 receptor in complex with doxepin[11] will likely increase the quality of novel structural H4 receptor models.[12] [13]

Ligands

Although the effectiveness of H4 receptor ligands has been studied in animal models and human biological samples, further research is needed to understand genetic polymorphisms and interspecies differences in their actions and pharmacological characteristics.

Agonists

Antagonists

Therapeutic potential

The available data support the H4 receptor as a promising new drug target for modulating histamine-mediated immune signaling and offer optimistic prospects for developing new therapies for inflammatory diseases.[14]

H4 receptor antagonists could be used to treat asthma and allergies.[15]

The highly selective histamine H4 antagonist VUF-6002 is orally active and inhibits the activity of both mast cells and eosinophils in vivo,[16] and has anti-inflammatory and antihyperalgesic effects.[17]

See also

Notes and References

  1. Oda T, Morikawa N, Saito Y, Masuho Y, Matsumoto S . Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes . J. Biol. Chem. . 275 . 47 . 36781–6 . 2000 . 10973974 . 10.1074/jbc.M006480200 . free .
  2. Nakamura T, Itadani H, Hidaka Y, Ohta M, Tanaka K . Molecular cloning and characterization of a new human histamine receptor, HH4R . Biochem. Biophys. Res. Commun. . 279 . 2 . 615–20 . 2000 . 11118334 . 10.1006/bbrc.2000.4008 .
  3. Bryan Roth . Nguyen T, Shapiro DA, George SR, Setola V, Lee DK, Cheng R, Rauser L, Lee SP, Lynch KR, Roth BL, O'Dowd BF . Discovery of a novel member of the histamine receptor family . Mol. Pharmacol. . 59 . 3 . 427–33 . 2001 . 11179435 . 10.1124/mol.59.3.427. abstract .
  4. Oda T, Morikawa N, Saito Y, Masuho Y, Matsumoto S. Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes . J. Biol. Chem. . 275 . 47 . 36781–36786 . 2000 . 10.1074/jbc.M006480200 . 10973974. free .
  5. Takeshita K, Bacon KB, Gantner F . Critical role of L-selectin and histamine H4 receptor in zymosan-induced neutrophil recruitment from the bone marrow: comparison with carrageenan . J. Pharmacol. Exp. Ther. . 310 . 1 . 272–80 . 2004 . 14996947 . 10.1124/jpet.103.063776 . 6698467 .
  6. Salem A, Rozov S, Al-Samadi A, et al. Histamine metabolism and transportare deranged in human keratinocytes in oral lichen planus. Br J Dermatol. 2016. Available at: https://dx.doi.org/10.1111/bjd.14995.
  7. Hofstra CL, Desai PJ, Thurmond RL, Fung-Leung WP . Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells . J. Pharmacol. Exp. Ther. . 305 . 3 . 1212–21 . 2003 . 12626656 . 10.1124/jpet.102.046581 . 14932773 .
  8. Shin N, Coates E, Murgolo NJ, Morse KL, Bayne M, Strader CD, Monsma FJ . Molecular modeling and site-specific mutagenesis of the histamine-binding site of the histamine H4 receptor . Mol. Pharmacol. . 62 . 1 . 38–47 . July 2002 . 12065753 . 10.1124/mol.62.1.38. 16628657 .
  9. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M . Crystal structure of rhodopsin: A G protein-coupled receptor . Science . 289 . 5480 . 739–45 . August 2000 . 10926528 . 10.1126/science.289.5480.739. 2000Sci...289..739P . 10.1.1.1012.2275 .
  10. Kiss R, Kiss B, Könczöl A, Szalai F, Jelinek I, László V, Noszál B, Falus A, Keseru GM . Discovery of novel human histamine H4 receptor ligands by large-scale structure-based virtual screening . J. Med. Chem. . 51 . 11 . 3145–53 . June 2008 . 18459760 . 10.1021/jm7014777.
  11. Shimamura T, Shiroishi M, Weyand S, Tsujimoto H, Winter G, Katritch V, Abagyan R, Cherezov V, Liu W, Han GW, Kobayashi T, Stevens RC, Iwata S . Structure of the human histamine H(1) receptor complex with doxepin . Nature . 475. 7354. 65–70. June 2011 . 21697825 . 10.1038/nature10236 . 3131495.
  12. Schultes S, Nijmeijer S, Engelhardt H, Kooistra AJ, Vischer HF, de Esch IJ, Haaksma EJ, Leurs R, de Graaf C . Mapping histamine H4 receptor-ligand binding modes . MedChemComm . 4 . 193–204 . 2013 . 10.1039/C2MD20212C .
  13. Nijmeijer S, Engelhardt H, Schultes S, van de Stolpe AC, Lusink V, de Graaf C, Wijtmans M, Haaksma EE, de Esch IJ, Stachurski K, Vischer HF, Leurs R . Design and pharmacological characterization of VUF14480, a covalent partial agonist that interacts with cysteine 98(3.36) of the human histamine H4 receptor. . Br J Pharmacol . 170 . 1 . 89–100. 2013 . 23347159 . 10.1111/bph.12113. 3764852.
  14. Zampeli E, Tiligada E . The role of histamine H4 receptor in immune and inflammatory disorders . Br J Pharmacol . 157 . 1 . 24–33 . May 2009 . 19309354 . 2697784 . 10.1111/j.1476-5381.2009.00151.x.
  15. http://www.ebi.ac.uk/interpro/IEntry?ac=IPR008102 InterPro: IPR008102 Histamine H4 receptor
  16. Varga C, Horvath K, Berko A, Thurmond RL, Dunford PJ, Whittle BJ . Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat . European Journal of Pharmacology . 522 . 1-3 . 130–138 . October 2005 . 16213481 . 10.1016/j.ejphar.2005.08.045 .
  17. Coruzzi G, Adami M, Guaita E, de Esch IJ, Leurs R . Antiinflammatory and antinociceptive effects of the selective histamine H4-receptor antagonists JNJ7777120 and VUF6002 in a rat model of carrageenan-induced acute inflammation . European Journal of Pharmacology . 563 . 1-3 . 240–244 . June 2007 . 17382315 . 10.1016/j.ejphar.2007.02.026 .

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