HRH4

Official Full Name

histamine receptor H4

Organism

Homo sapiens

GeneID

59340

Background

Histamine is a ubiquitous messenger molecule released from mast cells, enterochromaffin-like cells, and neurons. Its various actions are mediated by a family of histamine receptors, which are a subset of the G-protein coupled receptor superfamily. This gene encodes a histamine receptor that is predominantly expressed in haematopoietic cells. The protein is thought to play a role in inflammation and allergy reponses. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

Synonyms

H4; H4R; BG26; HH4R; AXOR35; GPRv53; GPCR105;

Bio Chemical Class

GPCR rhodopsin

Protein Sequence

MPDTNSTINLSLSTRVTLAFFMSLVAFAIMLGNALVILAFVVDKNLRHRSSYFFLNLAISDFFVGVISIPLYIPHTLFEWDFGKEICVFWLTTDYLLCTASVYNIVLISYDRYLSVSNAVSYRTQHTGVLKIVTLMVAVWVLAFLVNGPMILVSESWKDEGSECEPGFFSEWYILAITSFLEFVIPVILVAYFNMNIYWSLWKRDHLSRCQSHPGLTAVSSNICGHSFRGRLSSRRSLSASTEVPASFHSERQRRKSSLMFSSRTKMNSNTIASKMGSFSQSDSVALHQREHVELLRARRLAKSLAILLGVFAVCWAPYSLFTIVLSFYSSATGPKSVWYRIAFWLQWFNSFVNPLLYPLCHKRFQKAFLKIFCIKKQPLPSQHSRSVSS

Open

Disease

Asthma, Atopic eczema, Mild neurocognitive disorder, Postoperative inflammation, Psoriasis, Rheumatoid arthritis, Vasomotor/allergic rhinitis

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

1 +

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Detailed Information

Histamine is a biologically active molecule that is found in many cells in the body, including neurons, mast cells, and enterochromaffin cells. By binding to four main histamine receptors (H1, H2, H3, H4), histamine helps control many normal and disease processes. The histamine H4 receptor (HRH4) is a G-protein coupled receptor that is very important in many types of immune cells, especially when it comes to controlling immune responses, inflammatory reactions, and allergic reactions. Finding HRH4 receptors and studying how they work has given us new information about how the immune system works and could lead to new treatments for immune diseases that are linked.

Structure and Function of the HRH4 Receptor

HRH4 is a member of the G-protein coupled receptor (GPCR) family and is primarily expressed in immune system cells, including eosinophils, dendritic cells, mast cells, and T cells. Compared to other histamine receptors, HRH4 differs significantly in both gene sequence and structure, especially when compared to H1 and H2 receptors. However, it shares a higher similarity with the H3 receptor in certain regions.

HRH4 receptors, upon binding to histamine, activate Gai/o proteins and induce changes in intracellular calcium ion concentrations, thereby regulating immune cell migration, activation, and cytokine secretion. Additionally, HRH4 modulates cAMP levels inside the cell, influencing immune cell function and inflammatory responses. The activity of HRH4 receptors is closely associated with the chemotaxis of immune cells, allowing it to serve as a key regulator in immune responses.

What makes HRH4 unique is that it plays different roles in different immune cell types. For example, in some immune cells, HRH4 activation may intensify chemotaxis, while in others, it may affect the nature of immune responses by regulating cytokine release.

Figure 1 illustrates the immunomodulatory actions of histamine that are mediated through H4 receptors predominantly expressed in immune cells. Figure 1. Indicative immunomodulatory actions of histamine that are mediated through histamine H4 receptors (H4) are predominately expressed in immune cells. (Zampeli E, et al., 2009)

The Critical Role of HRH4 in Immune Responses

Especially in terms of how immune cells migrate, get activated, and produce cytokines, HRH4 receptors are quite important in immunological responses. Activating HRH4 can significantly influence how effectively the immune system functions since it is present in many different kinds of immune cells.

Eosinophils are quite crucial for allergy responses and certain immune disorders. Eosinophils are significant for regulating the chemotactic responses histamine produces since they have several HRH4 receptors. Histamine binds to HRH4 receptors on eosinophils, hence enabling their migration to inflammatory sites and enhancing the response of the immune system there. Particularly for asthma and allergic rhinitis, this approach aggravates allergic conditions.

Important effector cells in the immune system, mast cells participate in various immunological responses. Mast cells' production of HRH4 receptors increases chemotaxis, hence enabling them to migrate to inflammatory sites. Activated HRH4 receptors do not trigger mast cells to produce granules like H1 receptors do. Rather, they alter their function, hence influencing their function in immunological responses. Controlling mast cell activity, HRH4 receptors are crucial for triggering allergic reactions. This is particularly true in situations of persistent allergic irritation.

Dendritic cells are significant since they display antigens and are at the core of immune reactions. HRH4 receptors have a major impact on the movement and antigen presentation of dendritic cells when they are activated. HRH4-expressing dendritic cells can migrate to sites of immunological activity and regulate which immune cells are activated and which ones develop. Moreover, by regulating the cytokines produced by dendritic cells, HRH4 receptors can alter the T cell immunological response. This regulates the ratio of TH1 to TH2 cells and modifies the kind of immunological response.

HRH4 Receptor in Immune Diseases and Potential Therapeutic Applications

Knowing that HRH4 has a role in autoimmune disorders, chronic inflammatory diseases, and allergy diseases is crucial. HRH4 receptors and their impact on allergic lung inflammation have been the subject of many studies. A powerful immunological mediator, histamine stimulates immune cells via HRH4 receptors. This causes inflammation in the lungs to worsen and encourages immune cells to migrate there. Activated HRH4 receptors in allergic airway disorders including asthma exacerbate immunological responses in the airways. This causes the airways to become more constricted, alter form, and more difficult to breathe. Developing medications aimed at HRH4 receptors provides fresh avenues for managing asthmatic allergic lung diseases.

Studies have also examined HRH4 receptor function in persistent itching, atopic dermatitis, and eczema among other allergic skin disorders. Histamine regulates the defense mechanism in the skin through its action on HRH4 receptors, which causes swelling and itching. HRH4 receptor blockers have shown to be very successful in animal models of allergic skin disorders including itching. This implies that HRH4 might be a novel target for managing these disorders.

The function of HRH4 in some inflammatory disorders has also received much attention. Autoimmune diseases are characterized by an overactive immune system and chronic inflammation. HRH4 receptors might significantly influence how autoimmune diseases begin and progress by altering the movement and cytokine release of immune cells. Studies have shown that those with rheumatoid arthritis, systemic lupus erythematosus, and other inflammatory disorders had elevated HRH4 levels. This suggests that HRH4 might be a suitable target for managing these disorders.

References:

Im D, Kishikawa JI, Shiimura Y, et al. Structural insights into the agonists binding and receptor selectivity of human histamine H4 receptor. Nat Commun. 2023;14(1):6538.
Kaneko H, Ye F, et al. Histamine H4 receptor as a new therapeutic target for choroidal neovascularization in age-related macular degeneration. Br J Pharmacol. 2014 Aug;171(15):3754-63.
Zampeli E, Tiligada E. The role of histamine H4 receptor in immune and inflammatory disorders. Br J Pharmacol. 2009 May;157(1):24-33.

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