Histamine H4 receptor

Unlike the histamine receptors discovered earlier, H₄ was found in 2000 through a search of the human genomic DNA data base.{{cite journal |vauthors=Oda T, Morikawa N, Saito Y, Masuho Y, Matsumoto S|title=Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes |journal=J. Biol. Chem. |volume=275 |number=47 |pages=36781–36786 |year=2000 |doi=10.1074/jbc.M006480200 |pmid=10973974|doi-access=free }}

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.{{cite journal |vauthors=Takeshita K, Bacon KB, Gantner F | title = Critical role of L-selectin and histamine H4 receptor in zymosan-induced neutrophil recruitment from the bone marrow: comparison with carrageenan | journal = J. Pharmacol. Exp. Ther. | volume = 310 | issue = 1 | pages = 272–80 | year = 2004 | pmid = 14996947 | doi = 10.1124/jpet.103.063776 | s2cid = 6698467 }} It was also found that H₄ receptor exhibits a uniform expression pattern in the human oral epithelium.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.

The Histamine H₄ receptor has been shown to be involved in mediating eosinophil shape change and mast cell chemotaxis.{{cite journal |vauthors=Hofstra CL, Desai PJ, Thurmond RL, Fung-Leung WP | title = Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells | journal = J. Pharmacol. Exp. Ther. | volume = 305 | issue = 3 | pages = 1212–21 | year = 2003 | pmid = 12626656 | doi = 10.1124/jpet.102.046581 | s2cid = 14932773 }} This occurs via the βγ subunit acting at phospholipase C to cause actin polymerization and eventually chemotaxis.

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.

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{{cite journal |vauthors=Shin N, Coates E, Murgolo NJ, Morse KL, Bayne M, Strader CD, Monsma FJ | title = Molecular modeling and site-specific mutagenesis of the histamine-binding site of the histamine H4 receptor | journal = Mol. Pharmacol. | volume = 62 | issue = 1 | pages = 38–47 |date=July 2002 | pmid = 12065753 | doi = 10.1124/mol.62.1.38| s2cid = 16628657 }} was built by homology modelling based on the crystal structure of bovine rhodopsin.{{cite journal |vauthors=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 | title = Crystal structure of rhodopsin: A G protein-coupled receptor | journal = Science | volume = 289 | issue = 5480 | pages = 739–45 |date=August 2000 | pmid = 10926528 | doi = 10.1126/science.289.5480.739| bibcode = 2000Sci...289..739P | citeseerx = 10.1.1.1012.2275 }} 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.{{cite journal |vauthors=Kiss R, Kiss B, Könczöl A, Szalai F, Jelinek I, László V, Noszál B, Falus A, Keseru GM | title = Discovery of novel human histamine H4 receptor ligands by large-scale structure-based virtual screening | journal = J. Med. Chem. | volume = 51 | issue = 11 | pages = 3145–53 |date=June 2008 | pmid = 18459760 | doi = 10.1021/jm7014777}}

• {{cite web |author=Robert Kiss |date=June 16, 2011 |title=The road to mcule |website=Mcule |type=Blog |url=http://blog.mcule.com/2011/06/as-first-post-in-mcule-blog-we-thought.html}}

Recent advancements in GPCR crystallization, in particular the determination of the human histamine H₁ receptor in complex with doxepin{{cite journal |vauthors=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 | title = Structure of the human histamine H(1) receptor complex with doxepin | journal = Nature | volume = 475| issue = 7354| pages = 65–70|date=June 2011 | pmid = 21697825 | doi = 10.1038/nature10236 | pmc=3131495}} will likely increase the quality of novel structural H₄ receptor models.{{cite journal |vauthors=Schultes S, Nijmeijer S, Engelhardt H, Kooistra AJ, Vischer HF, de Esch IJ, Haaksma EJ, Leurs R, de Graaf C | title = Mapping histamine H₄ receptor-ligand binding modes | journal = MedChemComm | volume = 4 | pages = 193–204 | year = 2013 | doi = 10.1039/C2MD20212C }}{{cite journal |vauthors=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 | title = Design and pharmacological characterization of VUF14480, a covalent partial agonist that interacts with cysteine 98(3.36) of the human histamine H₄ receptor. | journal = Br J Pharmacol | volume = 170 | issue = 1 | pages = 89–100| year = 2013 | pmid = 23347159 | doi = 10.1111/bph.12113| pmc = 3764852}}

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.

• 4-Methylhistamine
• VUF-8430 (2-[(Aminoiminomethyl)amino]ethyl carbamimidothioic acid ester)
• OUP-16
• Clozapine
• JNJ 28610244

• Toreforant (JNJ 38518168)
• Mianserin (also a H1 and H3 antagonist)
• Thioperamide (also a selective H3 antagonist)
• JNJ 7777120 (discontinued)
• JNJ 39758979 (discontinued)
• ZPL389
• VUF-6002 (1-[(5-Chloro-1H-benzimidazol-2-yl)carbonyl]-4-methylpiperazine)
• A987306
• A943931
• Pimozide

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.{{cite journal |vauthors=Zampeli E, Tiligada E |title=The role of histamine H4 receptor in immune and inflammatory disorders |journal=Br J Pharmacol |volume=157 |issue=1 |pages=24–33 |date=May 2009 |pmid=19309354 |pmc=2697784 |doi=10.1111/j.1476-5381.2009.00151.x}}

H₄ receptor antagonists could be used to treat asthma and allergies.[http://www.ebi.ac.uk/interpro/IEntry?ac=IPR008102 InterPro: IPR008102 Histamine H4 receptor]

The highly selective histamine H₄ antagonist VUF-6002 is orally active and inhibits the activity of both mast cells and eosinophils in vivo,{{cite journal | vauthors = Varga C, Horvath K, Berko A, Thurmond RL, Dunford PJ, Whittle BJ | title = Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat | journal = European Journal of Pharmacology | volume = 522 | issue = 1-3 | pages = 130–138 | date = October 2005 | pmid = 16213481 | doi = 10.1016/j.ejphar.2005.08.045 }} and has anti-inflammatory and antihyperalgesic effects.{{cite journal | vauthors = Coruzzi G, Adami M, Guaita E, de Esch IJ, Leurs R | title = Antiinflammatory and antinociceptive effects of the selective histamine H4-receptor antagonists JNJ7777120 and VUF6002 in a rat model of carrageenan-induced acute inflammation | journal = European Journal of Pharmacology | volume = 563 | issue = 1-3 | pages = 240–244 | date = June 2007 | pmid = 17382315 | doi = 10.1016/j.ejphar.2007.02.026 }}

• Histamine H₁-receptor
• Histamine H₂-receptor
• Histamine H₃-receptor

{{Reflist|2}}

• {{MeshName|HRH4+protein,+human}}

{{G protein-coupled receptors}}

{{Histaminergics}}

Category:Histamine receptors