Histamine H4 receptor
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The histamine H4 receptor is, like the other three histamine receptors, a member of the G protein-coupled receptor superfamily.[1][2][3]
Contents
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
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<references />, or <references group="..." />External links
- HRH4 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
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- ↑ Bioreagents.com: Histamine H4 Receptor
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- ↑ InterPro: IPR008102 Histamine H4 receptor
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