Histamine H₄ receptor

HRH4
Identifiers
Aliases	HRH4, AXOR35, BG26, GPCR105, GPRv53, H4, H4R, HH4R, histamine receptor H4
External IDs	OMIM: 606792; MGI: 2429635; HomoloGene: 11002; GeneCards: HRH4; OMA:HRH4 - orthologs
Gene location (Human)
Chr.	Chromosome 18 (human)
End	24,479,961 bp
Gene location (Mouse)
Chr.	Chromosome 18 (mouse)
End	13,155,939 bp
RNA expression pattern
	Top expressed in
	monocyte; ; bone marrow; ; gonad; ; tibialis anterior muscle; ; blood; ; appendix; ; deltoid muscle; ; duodenum; ; right lobe of liver; ; lymph node;
	Top expressed in
	embryo; ; spermatocyte; ; spermatid; ; vastus lateralis muscle; ; testicle; ; thymus;
	More reference expression data
	n/a
Gene ontology
Molecular function	G protein-coupled receptor activity; signal transducer activity; histamine receptor activity; G protein-coupled serotonin receptor activity; G protein-coupled acetylcholine receptor activity; neurotransmitter receptor activity;
Cellular component	integral component of membrane; membrane; plasma membrane; integral component of plasma membrane; dendrite;
Biological process	positive regulation of cytosolic calcium ion concentration; regulation of MAPK cascade; signal transduction; inflammatory response; negative regulation of adenylate cyclase activity; G protein-coupled receptor signaling pathway; biological process; G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger; adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway; chemical synaptic transmission; G protein-coupled serotonin receptor signaling pathway;
	Sources:Amigo / QuickGO
Orthologs
	59340
	225192
	ENSG00000134489
	ENSMUSG00000037346
	Q9H3N8
	Q91ZY2
	NM_001143828; NM_001160166; NM_021624
	NM_153087
	NP_001137300; NP_001153638; NP_067637
	NP_694727
	Wikidata
View/Edit Human	View/Edit Mouse

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.^[5]^[6]^[7]

Discovery

Unlike the histamine receptors discovered earlier, H₄ was found in 2000 through a search of the human genomic DNA data base.^[8]

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.^[9] It was also found that H₄ receptor exhibits a uniform expression pattern in the human oral epithelium.^[10]

Function

The Histamine H₄ receptor has been shown to be involved in mediating eosinophil shape change and mast cell chemotaxis.^[11] This occurs via the βγ subunit acting at phospholipase C to cause actin polymerization and eventually chemotaxis.^[11]

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.^[12]

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^[13] was built by homology modelling based on the crystal structure of bovine rhodopsin.^[14] 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.^[15]

Recent advancements in GPCR crystallization, in particular the determination of the human histamine H₁ receptor in complex with doxepin^[16] will likely increase the quality of novel structural H₄ receptor models.^[17]^[18]

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.^[12]

Agonists

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

Antagonists

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

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.^[12]

H₄ receptor antagonists could be used to treat asthma and allergies.^[19]

The highly selective histamine H₄ antagonist VUF-6002 is orally active and inhibits the activity of both mast cells and eosinophils in vivo,^[20] and has anti-inflammatory and antihyperalgesic effects.^[21]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000134489 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000037346 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ 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.
^ 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.
^ Nguyen T, Shapiro DA, George SR, Setola V, Lee DK, Cheng R, et al. (2001). "Discovery of a novel member of the histamine receptor family" (abstract). Mol. Pharmacol. 59 (3): 427–33. doi:10.1124/mol.59.3.427. PMID 11179435.
^ 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.
^ 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. S2CID 6698467.
^ 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.
^ ^a ^b 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. S2CID 14932773.
^ ^a ^b ^c Zampeli E, Tiligada E (May 2009). "The role of histamine H4 receptor in immune and inflammatory disorders". Br J Pharmacol. 157 (1): 24–33. doi:10.1111/j.1476-5381.2009.00151.x. PMC 2697784. PMID 19309354.
^ Shin N, Coates E, Murgolo NJ, Morse KL, Bayne M, Strader CD, et al. (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. S2CID 16628657.
^ Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, et al. (August 2000). "Crystal structure of rhodopsin: A G protein-coupled receptor". Science. 289 (5480): 739–45. Bibcode:2000Sci...289..739P. CiteSeerX 10.1.1.1012.2275. doi:10.1126/science.289.5480.739. PMID 10926528.
^
Kiss R, Kiss B, Könczöl A, Szalai F, Jelinek I, László V, et al. (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.
- Robert Kiss (June 16, 2011). "The road to mcule". Mcule (Blog).
^ Shimamura T, Shiroishi M, Weyand S, Tsujimoto H, Winter G, Katritch V, et al. (June 2011). "Structure of the human histamine H(1) receptor complex with doxepin". Nature. 475 (7354): 65–70. doi:10.1038/nature10236. PMC 3131495. PMID 21697825.
^ Schultes S, Nijmeijer S, Engelhardt H, Kooistra AJ, Vischer HF, de Esch IJ, et al. (2013). "Mapping histamine H₄ receptor-ligand binding modes". MedChemComm. 4: 193–204. doi:10.1039/C2MD20212C.
^ Nijmeijer S, Engelhardt H, Schultes S, van de Stolpe AC, Lusink V, de Graaf C, et al. (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.
^ InterPro: IPR008102 Histamine H4 receptor
^ Varga C, Horvath K, Berko A, Thurmond RL, Dunford PJ, Whittle BJ (October 2005). "Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat". European Journal of Pharmacology. 522 (1–3): 130–138. doi:10.1016/j.ejphar.2005.08.045. PMID 16213481.
^ Coruzzi G, Adami M, Guaita E, de Esch IJ, Leurs R (June 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): 240–244. doi:10.1016/j.ejphar.2007.02.026. PMID 17382315.

External links

HRH4+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000134489 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000037346 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid10973974-5] 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.

[pmid11118334-6] 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.

[pmid11179435-7] Nguyen T, Shapiro DA, George SR, Setola V, Lee DK, Cheng R, et al. (2001). "Discovery of a novel member of the histamine receptor family" (abstract). Mol. Pharmacol. 59 (3): 427–33. doi:10.1124/mol.59.3.427. PMID 11179435.

[8] 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.

[pmid14996947-9] 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. S2CID 6698467.

[10] 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.

[pmid12626656-11] 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. S2CID 14932773.

[pmid19309354-12] Zampeli E, Tiligada E (May 2009). "The role of histamine H4 receptor in immune and inflammatory disorders". Br J Pharmacol. 157 (1): 24–33. doi:10.1111/j.1476-5381.2009.00151.x. PMC 2697784. PMID 19309354.

[pmid12065753-13] Shin N, Coates E, Murgolo NJ, Morse KL, Bayne M, Strader CD, et al. (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. S2CID 16628657.

[pmid10926528-14] Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, et al. (August 2000). "Crystal structure of rhodopsin: A G protein-coupled receptor". Science. 289 (5480): 739–45. Bibcode:2000Sci...289..739P. CiteSeerX 10.1.1.1012.2275. doi:10.1126/science.289.5480.739. PMID 10926528.

[pmid18459760-15] Kiss R, Kiss B, Könczöl A, Szalai F, Jelinek I, László V, et al. (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.
Robert Kiss (June 16, 2011). "The road to mcule". Mcule (Blog).

[16] Robert Kiss (June 16, 2011). "The road to mcule". Mcule (Blog).

[pmid21697825-16] Shimamura T, Shiroishi M, Weyand S, Tsujimoto H, Winter G, Katritch V, et al. (June 2011). "Structure of the human histamine H(1) receptor complex with doxepin". Nature. 475 (7354): 65–70. doi:10.1038/nature10236. PMC 3131495. PMID 21697825.

[Schultes_2013-17] Schultes S, Nijmeijer S, Engelhardt H, Kooistra AJ, Vischer HF, de Esch IJ, et al. (2013). "Mapping histamine H₄ receptor-ligand binding modes". MedChemComm. 4: 193–204. doi:10.1039/C2MD20212C.

[pmid23347159-18] Nijmeijer S, Engelhardt H, Schultes S, van de Stolpe AC, Lusink V, de Graaf C, et al. (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.

[interpro-19] InterPro: IPR008102 Histamine H4 receptor

[20] Varga C, Horvath K, Berko A, Thurmond RL, Dunford PJ, Whittle BJ (October 2005). "Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat". European Journal of Pharmacology. 522 (1–3): 130–138. doi:10.1016/j.ejphar.2005.08.045. PMID 16213481.

[21] Coruzzi G, Adami M, Guaita E, de Esch IJ, Leurs R (June 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): 240–244. doi:10.1016/j.ejphar.2007.02.026. PMID 17382315.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]