Histamine H4 receptor

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. 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 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

Antagonists

Therapeutic potential

By inhibiting the H₄ receptor, asthma and allergy may be treated.

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