Unlike the histamine receptors discovered earlier, H4 was found in 2000 through a search of the human genomic DNA data base.
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. It was also found that H4R exhibits a uniform expression pattern in the human oral epithelium. 
The Histamine H4 receptor has been shown to be involved in mediating eosinophil shape change and mast cell chemotaxis. 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 was built by homology modelling based on the crystal structure of bovine rhodopsin. 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.
Recent advancements in GPCR crystallization, in particular the determination of the human histamine H1 receptor in complex with doxepin will likely increase the quality of novel structural H4 receptor models.
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^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. PMID10973974.
^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. PMID18459760. Lay summary – blog.mcule.com.
^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. PMID16213481.
^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. PMID17382315.