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 was also found that H₄ receptor exhibits a uniform expression pattern in the human oral epithelium.

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 polymerization and eventually chemotaxis.

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.

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.

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.

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.

H₄ receptor antagonists could be used to treat asthma and allergies.

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 anti-inflammatory and antihyperalgesic effects.