HRH4 Membrane Protein Introduction

Introduction of HRH4

Histamine H4 receptor (H4R or HRH4), is an integral membrane protein which in human is encoded by HRH4 gene. It is recognized as a histamine receptor belonging to the family of rhodopsin-like G-protein-coupled receptors. HRH4 is predominantly expressed in bone marrow and shows generally restricted expression in immune cells. It is also expressed in the liver, colon, lung, spleen, small intestine, testes, tonsils, thymus, and trachea. It is also found in the cerebellum and hippocampus. The expression of HRH4 is either up-regulated or down-regulated upon activation of the lymphoid tissues and this regulation may rely on the presence of IL10/interleukin-10 or IL13/interleukin-13.

Basic Information of HRH4
Protein Name Histamine H4 receptor
Gene Name HRH4
Aliases H4, H4R, BG26, HH4R, AXOR35, GPRv53, GPCR105
Organism Homo sapiens (Human)
UniProt ID Q9H3N8
Transmembrane Times 7
Length (aa) 390

Function of HRH4 Membrane Protein

Histamine affects its functions in the microcirculation by stimulating heptahelical receptors. HRH4 has been demonstrated to mediate histamine induced-chemotaxis, indicating that it may play a role in inflammation. Since H4 stimulation can cause chemotaxis of mast cells and HRH4 is preferentially expressed on hematopoietic and immunocompetent cells, HRH4 is proved to be responsible for mast/eosinophil chemotaxis and recruitment, thereby amplifying histamine-mediated allergic reactions. This process occurs the βγ subunit acting at phospholipase C to cause actin polymerization and eventually chemotaxis. HRH4 has also shown to play a critical role in inflammatory diseases, including rheumatoid arthritis, asthma, pruritis, and inflammatory pain. Multiple H4R antagonists have been discovered and characterized, which shown efficacy in numerous preclinical models of inflammation. Numerous studies have emphasized the importance of targeting this receptor as a novel therapeutic in inflammation.

Proposed role of histamine H1 and H4 receptors in peripheral and central transmission of itch responses. Fig.1 Proposed role of histamine H1 and H4 receptors in peripheral and central transmission of itch responses. (Thurmond, 2008)

Application of HRH4 Membrane Protein in Literature

  1. Yamamoto K., et al. Effects of a histamine H4 receptor antagonist on cisplatin-induced anorexia in mice. Neurosci Lett. 2018, 676:103-107. PubMed ID: 29655943

    The results of this article suggested that TNF-α mRNA expression via H4 receptors may contribute to the development of cisplatin-induced anorexia, and that H4 receptor antagonists were potentially useful treatments.

  2. Mommert S., et al. The histamine H4 receptor modulates the differentiation process of human monocyte-derived M1 macrophages and the release of CCL4/MIP-1β from fully differentiated M1 macrophages. Inflamm Res. 2018, 67(6):503-513. PubMed ID: 29600327

    This study was carried out to describe novel immunomodulatory functions of the H4R during the differentiation process of human monocyte-derived macrophages and in fully differentiated M1 macrophages.

  3. Ko K., et al. Discovery of a novel highly selective histamine H4 receptor antagonist for the treatment of atopic dermatitis. J Med Chem. 2018, 61(7):2949-2961. PubMed ID: 29579390

    Authors of this article discovered a novel class of orally available H4R antagonists showing strong anti-itching and anti-inflammation activity as well as excellent selectivity against off-targets. They found that an orally administered compound exhibited remarkable efficacy on anti-pruritus and anti-inflammation with a favorable pharmacokinetic (PK) profile in several mouse models of AD (atopic dermatitis).

  4. Huang K., et al. persistent extracellular signal-regulated kinase activation by the histamine H4 receptor in spinal neurons underlies chronic itch. J Invest Dermatol. 2018. PubMed ID: 29486155

    The findings indicated that persistent ERK (extracellular signal-regulated kinase) activation via the histamine H4 receptor in spinal neurons underlied DNFB-induced chronic itch.

  5. Abiuso A. M. B., et al. Histamine H4 receptor as a novel therapeutic target for the treatment of Leydig-cell tumours in prepubertal boys. Eur J Cancer. 2018, 91:125-135. PubMed ID: 29367056

    This article investigated the potential role of the histamine receptor H4 (HRH4) as a therapeutic target for LCTs using R2C rat Leydig tumor cells, a well-documented in vitro model for Leydigioma. The results pointed to HRH4 as a novel therapeutic target in LCTs.

HRH4 Preparation Options

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  1. Thurmond R L., et al. (2008). The role of histamine H 1 and H 4 receptors in allergic inflammation: the search for new antihistamines. Nature reviews Drug discovery. 7(1), 41.

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