Histamine H4 receptor

Histamine receptor H4
Identifiers
Symbols	HRH4 ; AXOR35; BG26; GPCR105; GPRv53; H4; H4R; HH4R
External IDs	OMIM: 606792 MGI: 2429635 HomoloGene: 11002 IUPHAR: 265 ChEMBL: 3759 GeneCards: HRH4 Gene
Gene ontology Molecular function • histamine receptor activity • histamine binding Cellular component • cytosol • plasma membrane • integral component of plasma membrane Biological process • inflammatory response • negative regulation of adenylate cyclase activity • positive regulation of cytosolic calcium ion concentration • sensory perception of chemical stimulus • biological_process • positive regulation of adenylate cyclase activity involved in G-protein coupled receptor signaling pathway • regulation of MAPK cascade Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	59340	225192
Ensembl	ENSG00000134489	ENSMUSG00000037346
UniProt	Q9H3N8	Q91ZY2
RefSeq (mRNA)	NM_001143828	NM_153087
RefSeq (protein)	NP_001137300	NP_694727
Location (UCSC)	Chr 18: 24.46 – 24.48 Mb	Chr 18: 13.01 – 13.02 Mb
PubMed search

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

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.^[4] It is also expressed in the colon, liver, lung, small intestine, spleen, testes, thymus, tonsils, and trachea.^[5]

Function

The Histamine H4 receptor has been shown to be involved in mediating eosinophil shape change and mast cell chemotaxis.^[6] This occurs via the βγ subunit acting at phospholipase C to cause actin polymerisation and eventually chemotaxis.

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^[7] was built by homology modelling based on the crystal structure of bovine rhodopsin.^[8] 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.^[9]

Recent advancements in GPCR crystallization, in particular the determination of the human histamine H₁ receptor in complex with doxepin^[10] will likely increase the quality of novel structural H₄ receptor models.^[11][12]

Ligands

Agonists

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

Antagonists

• Thioperamide
• JNJ 7777120
• VUF-6002 (1-[(5-Chloro-1H-benzimidazol-2-yl)carbonyl]-4-methylpiperazine)
• A987306
• A943931

Therapeutic potential

By inhibiting the H₄ receptor, asthma and allergy may be treated.^[13]

The highly selective histamine H₄ antagonist VUF-6002 is orally active and inhibits the activity of both mast cells and eosinophils in vivo,^[14] and has antiinflammatory and antihyperalgesic effects.^[15]

References

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. 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.
5. Bioreagents.com: Histamine H4 Receptor
6. 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.
7. 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.
8. 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.
9. 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 summary – blog.mcule.com.
10. 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.
11. Schultes S, Nijmeijer S, Engelhardt H, Kooistra AJ, Vischer HF, de Esch IJP, Haaksma EJ, Leurs R, de Graaf C (2013). "Mapping histamine H₄ receptor-ligand binding modes". MedChemComm 4: 193–204. doi:10.1039/C2MD20212C.
12. 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. PMID 23347159.
13. InterPro: IPR008102 Histamine H4 receptor
14. 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.
15. 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.

External links

• HRH4 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)