Histamine H4 receptor

The histamine H4 receptor is, like the other three is_associated_with::histamine receptors, a member of the is_associated_with::G protein-coupled receptor superfamily.

Tissue distribution
H4 is highly expressed in bone marrow and white blood cells and regulates is_associated_with::neutrophil release from bone marrow and subsequent infiltration in the is_associated_with::zymosan-induced is_associated_with::pleurisy mouse model. It is also expressed in the colon, liver, lung, small intestine, spleen, testes, thymus, tonsils, and trachea.

Function
The Histamine H4 receptor has been shown to be involved in mediating eosinophil shape change and mast cell is_associated_with::chemotaxis. 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 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.

Agonists

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

Antagonists

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

Therapeutic potential
By inhibiting the H4 receptor, is_associated_with::asthma and is_associated_with::allergy may be treated.

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