HRH4 (Histamine Receptor H4): A Key Mediator of Immune and Inflammatory Responses
Comprehensive genetic, expression, and mutation analysis of the HRH4 gene, encoding the histamine H4 receptor, a promising therapeutic target for allergic and inflammatory diseases.
Gene Information Card
| Symbol | HRH4 |
|---|---|
| Full Name | Histamine Receptor H4 |
| Gene Type | protein coding |
| Chromosomal Location | 18q23 |
| NCBI Gene ID | 59340 ncbi.nlm.nih.gov/gene/59340 |
| Ensembl ID | ENSG00000145777 |
| UniProt ID | Q9H3N8 |
| OMIM ID | 606079 |
| HGNC ID | 17383 |
| Aliases | BG26, GPCR105, H4R, HH4R |
Description
The HRH4 gene encodes the histamine H4 receptor, a G-protein-coupled receptor (GPCR) that plays a crucial role in mediating histamine signaling in immune and inflammatory responses. It is primarily expressed on hematopoietic cells, including eosinophils, mast cells, dendritic cells, and T cells. Activation of HRH4 modulates various cellular functions such as chemotaxis, cytokine production, and cell proliferation. Due to its involvement in inflammatory processes, HRH4 has emerged as a promising therapeutic target for conditions like allergic rhinitis, asthma, and pruritus.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Disease | Mechanism | Evidence |
| Allergic Rhinitis | HRH4 activation on eosinophils and mast cells promotes chemotaxis and release of pro-inflammatory mediators, contributing to nasal inflammation. | Expression studies and animal models (e.g., HRH4 knockout mice show reduced eosinophil infiltration). |
| Asthma | HRH4 signaling in airway smooth muscle and immune cells contributes to airway inflammation and hyperresponsiveness. | Preclinical studies with HRH4 antagonists show reduced airway inflammation in mouse models. |
| Pruritus (Itching) | HRH4 expressed on sensory neurons and immune cells in the skin mediates histamine-induced itch, independent of H1 receptor. | Clinical trials with HRH4 antagonists (e.g., ZPL-3893787) have shown efficacy in reducing itch in atopic dermatitis. |
| Inflammatory Bowel Disease (IBD) | HRH4 expression is upregulated in inflamed colonic tissue, and its activation promotes inflammatory cytokine production. | Expression analysis in patient biopsies and animal models of colitis. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Tissue | nTPM | Level |
| Bone Marrow | 12.5 | Medium |
| Spleen | 8.9 | Low |
| Lymph Node | 7.2 | Low |
| Lung | 4.1 | Low |
| Small Intestine | 3.5 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Cell Line | nTPM | Notes |
| THP-1 (Monocytic leukemia) | 15.3 | High expression; used as a model for monocyte/macrophage function. |
| HL-60 (Promyeloblast) | 10.1 | Moderate expression; can be differentiated into granulocytes. |
| Jurkat (T cell leukemia) | 5.2 | Low expression; reflects T cell expression. |
| A549 (Lung carcinoma) | 1.8 | Very low expression; not a primary site of HRH4 expression. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| Variant | Type | Frequency | Effect |
| rs11662595 | SNV (Intronic) | ~30% (global) | Associated with altered HRH4 expression in some studies; functional significance unclear. |
| rs1421325 | SNV (5' UTR) | ~15% (global) | May affect mRNA stability or translation efficiency. |
| p.Arg341Cys (rs61742642) | Missense | <1% | Located in the third intracellular loop; may affect G-protein coupling and signaling. |
| p.Val169Ile (rs61742641) | Missense | <1% | Located in transmembrane domain 4; potential impact on ligand binding. |
Mutation functional classification
Loss of Function (LOF)
Mutations that impair HRH4 signaling, such as those affecting ligand binding or G-protein coupling, could reduce histamine-mediated immune responses. This might lead to altered inflammatory responses, potentially increasing susceptibility to infections or reducing allergic inflammation.
Gain of Function (GOF)
Gain-of-function mutations that enhance HRH4 signaling could lead to exaggerated inflammatory responses, contributing to chronic inflammation, autoimmunity, or heightened allergic reactions.
Dominant Negative (DN)
A dominant-negative HRH4 mutation could interfere with the function of the wild-type receptor, potentially by forming non-functional heterodimers or competing for downstream signaling molecules, thereby reducing overall histamine signaling.
View complete mutation data：
Gene Ontology (GO)
| • G protein-coupled receptor activity | • histamine receptor activity |
| • plasma membrane | • signal transduction |
| • G protein-coupled receptor signaling pathway | • immune response |
| • inflammatory response | • cell chemotaxis |
| • positive regulation of cytosolic calcium ion concentration |
Pathways
• Histamine signaling pathway
• GPCR downstream signaling
• Immune system signaling
• Inflammatory mediator regulation of TRP channels
Protein Summary
The HRH4 protein is a 390-amino acid integral membrane protein belonging to the rhodopsin-like G-protein-coupled receptor family. It shares approximately 30-40% sequence identity with the H3 receptor. HRH4 couples primarily to Gαi/o proteins, leading to inhibition of adenylyl cyclase, reduction of cAMP levels, and activation of MAP kinase pathways. It also mobilizes intracellular calcium. The receptor is characterized by seven transmembrane domains, an extracellular N-terminus, and an intracellular C-terminus. HRH4 is a key regulator of immune cell function, particularly in mediating chemotaxis of eosinophils and mast cells, and modulating cytokine release from dendritic cells and T cells.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| HRH4 Knockout HEK293 Cell Line | EDJ-KQ13778 | Human | 59340 | Details Get a Quote |
| HRH4 Knockout HeLa Cell Line | EDJ-KQ56967 | Human | 59340 | Details Get a Quote |
| HRH4 Knockout A-549 Cell Line | EDJ-KQ65470 | Human | 59340 | Details Get a Quote |
| HRH4 Knockout HCT 116 Cell Line | EDJ-KQ73908 | Human | 59340 | Details Get a Quote |
