The histamine H₄ receptor, like the other three

histamine receptors The histamine receptors are a class of G protein–coupled receptors which bind histamine as their primary endogenous ligand. There are four known histamine receptors: * H1 receptor * H2 receptor * H3 receptor * H4 receptor Comparison There ...

, is a member of the

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

superfamily that in humans is encoded by the ''HRH4''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

Discovery

Unlike the histamine receptors discovered earlier, H₄ was found in 2000 through a search of the human genomic DNA data base.

Tissue distribution

H₄ is highly expressed in bone marrow and white blood cells and regulates

neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...

release from bone marrow and subsequent infiltration in the

zymosan Zymosan is a glucan with repeating glucose units connected by β-1,3-glycosidic linkages. It binds to TLR 2 Toll-like receptor 2 also known as TLR2 is a protein that in humans is encoded by the ''TLR2'' gene. TLR2 has also been designated as CD ...

-induced

pleurisy Pleurisy, also known as pleuritis, is inflammation of the membranes that surround the lungs and line the chest cavity ( pleurae). This can result in a sharp chest pain while breathing. Occasionally the pain may be a constant dull ache. Other sy ...

mouse model. It was also found that H4R exhibits a uniform expression pattern in the human oral epithelium.

Function

The Histamine H4 receptor has been shown to be involved in mediating

eosinophil Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...

shape change and mast cell chemotaxis. This occurs via the βγ subunit acting at phospholipase C to cause actin polymerization 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.

Ligands

Agonists

* 4-Methylhistamine * VUF-8430 (2- Aminoiminomethyl)aminothyl carbamimidothioic acid ester) * OUP-16 *

Clozapine Clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic). It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate respo ...

* JNJ 28610244

Antagonists

* Toreforant (JNJ 38518168) *

Mianserin Mianserin, sold under the brand name Tolvon among others, is an atypical antidepressant that is used primarily in the treatment of depression in Europe and elsewhere in the world. It is a tetracyclic antidepressant (TeCA). Mianserin is closely ...

(also a H1 and H3 antagonist) * Thioperamide (also a selective H3 antagonist) *

JNJ 7777120 JNJ-7777120 was a drug being developed by Johnson & Johnson Pharmaceutical Research & Development which acts as a potent and selective antagonist at the histamine H4 receptor. It has anti-inflammatory effects, and has been demonstrated to be su ...

(discontinued) * JNJ 39758979 (discontinued) * ZPL389 * VUF-6002 (1- 5-Chloro-1H-benzimidazol-2-yl)carbonyl4-methylpiperazine) * A987306 * A943931 *

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Therapeutic potential

H₄ receptor antagonists could be used to treat

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...

and

allergies Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermat ...

.InterPro: IPR008102 Histamine H4 receptor
/ref> The highly selective histamine H₄ antagonist VUF-6002 is orally active and inhibits the activity of both

mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...

s and

s ''in vivo'', and has

anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...

and antihyperalgesic effects.

References

External links

* {{Histaminergics Histamine receptors