Histamine H4 receptor

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The histamine H4 receptor is, like the other three histamine receptors, a member of the G protein-coupled receptor superfamily.[1][2][3]


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 is also expressed in the colon, liver, lung, small intestine, spleen, testes, thymus, tonsils, and trachea.[6] It was also found that H4R exhibits a uniform expression pattern in the human oral epithelium. [7]


The Histamine H4 receptor has been shown to be involved in mediating eosinophil shape change and mast cell chemotaxis.[8] This occurs via the βγ subunit acting at phospholipase C to cause actin polymerisation and eventually chemotaxis.


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[9] was built by homology modelling based on the crystal structure of bovine rhodopsin.[10] 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.[11]

Recent advancements in GPCR crystallization, in particular the determination of the human histamine H1 receptor in complex with doxepin[12] will likely increase the quality of novel structural H4 receptor models.[13][14]




Therapeutic potential

By inhibiting the H4 receptor, asthma and allergy may be treated.[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 antiinflammatory and antihyperalgesic effects.[17]


  1. 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 (47): 36781–6. doi:10.1074/jbc.M006480200. PMID 10973974.
  2. 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 (2): 615–20. doi:10.1006/bbrc.2000.4008. PMID 11118334.
  3. 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" (abstract). Mol. Pharmacol. 59 (3): 427–33. PMID 11179435.
  4. 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 (47): 36781–36786. doi:10.1074/jbc.M006480200. PMID 10973974.
  5. Takeshita K, Bacon KB, Gantner F (2004). "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. doi:10.1124/jpet.103.063776. PMID 14996947.
  6. Bioreagents.com: Histamine H4 Receptor
  7. Salem A, Rozov S, Al-Samadi A, et al. Histamine metabolism and transport are deranged in human keratinocytes in oral lichen planus. Br J Dermatol. 2016. Available at: https://dx.doi.org/10.1111/bjd.14995.
  8. 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 (3): 1212–21. doi:10.1124/jpet.102.046581. PMID 12626656.
  9. Shin N, Coates E, Murgolo NJ, Morse KL, Bayne M, Strader CD, Monsma FJ (July 2002). "Molecular modeling and site-specific mutagenesis of the histamine-binding site of the histamine H4 receptor". Mol. Pharmacol. 62 (1): 38–47. doi:10.1124/mol.62.1.38. PMID 12065753.
  10. 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 (August 2000). "Crystal structure of rhodopsin: A G protein-coupled receptor". Science. 289 (5480): 739–45. doi:10.1126/science.289.5480.739. PMID 10926528.
  11. Kiss R, Kiss B, Könczöl A, Szalai F, Jelinek I, László V, Noszál B, Falus A, Keseru GM (June 2008). "Discovery of novel human histamine H4 receptor ligands by large-scale structure-based virtual screening". J. Med. Chem. 51 (11): 3145–53. doi:10.1021/jm7014777. PMID 18459760. Lay summaryblog.mcule.com.
  12. 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 (June 2011). "Structure of the human histamine H(1) receptor complex with doxepin". Nature. 475 (7354). doi:10.1038/nature10236. PMC 3131495. PMID 21697825.
  13. Schultes S, Nijmeijer S, Engelhardt H, Kooistra AJ, Vischer HF, de Esch IJ, Haaksma EJ, Leurs R, de Graaf C (2013). "Mapping histamine H4 receptor-ligand binding modes". MedChemComm. 4: 193–204. doi:10.1039/C2MD20212C.
  14. 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 (2013). "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. doi:10.1111/bph.12113. PMC 3764852. PMID 23347159.
  15. InterPro: IPR008102 Histamine H4 receptor
  16. Varga, C; Horvath, K; Berko, A; Thurmond, RL; Dunford, PJ; Whittle, BJ. (2005). "Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat". European Journal of Pharmacology. 522 (1–3): 130–8. doi:10.1016/j.ejphar.2005.08.045. PMID 16213481.
  17. Coruzzi, G; Adami, M; Guaita, E; de Esch, IJ; Leurs, R. (2007). "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): 240–4. doi:10.1016/j.ejphar.2007.02.026. PMID 17382315.

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