Histamine H4 receptor

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]

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)[1] Band 18q11.2 Start 24,460,637 bp[1] End 24,479,961 bp[1]
Gene location (Mouse) Chr. Chromosome 18 (mouse)[2] Band 18|18 A1 Start 13,140,047 bp[2] End 13,155,939 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) 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 BioGPS 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 Species Human Mouse Entrez 59340 225192 Ensembl ENSG00000134489 ENSMUSG00000037346 UniProt Q9H3N8 Q91ZY2 RefSeq (mRNA) NM_001143828 NM_001160166 NM_021624 NM_153087 RefSeq (protein) NP_001137300 NP_001153638 NP_067637 NP_694727 Location (UCSC) Chr 18: 24.46 – 24.48 Mb Chr 18: 13.14 – 13.16 Mb PubMed search [3] [4]
Wikidata
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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]

See also

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