The histamine H
4 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, H
4 was found in 2000 through a search of the human genomic DNA data base.
Tissue distribution
H
4 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 H
4 receptor for different purposes. The first H
4 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 H
4 receptor was successfully used for the identification of novel H
4 ligands.
[
*]
Recent advancements in GPCR crystallization, in particular the determination of the human histamine H
1 receptor in complex with doxepin
will likely increase the quality of novel structural H
4 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
*
Pimozide
Pimozide (sold under the brand name Orap) is an antipsychotic drug of the diphenylbutylpiperidine class. It was discovered at Janssen Pharmaceutica in 1963. It has a high potency compared to chlorpromazine (ratio 50-70:1). On a weight basis ...
Therapeutic potential
H
4 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](_blank)
/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 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 ...
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.
See also
* Histamine H1-receptor
* Histamine H2-receptor
* Histamine H3-receptor
References
External links
*
{{Histaminergics
Histamine receptors