HRH1

Official Full Name

histamine receptor H1

Organism

Homo sapiens

GeneID

3269

Background

Histamine is a ubiquitous messenger molecule released from mast cells, enterochromaffin-like cells, and neurons. Its various actions are mediated by histamine receptors H1, H2, H3 and H4. The protein encoded by this gene is an integral membrane protein and belongs to the G protein-coupled receptor superfamily. It mediates the contraction of smooth muscles, the increase in capillary permeability due to contraction of terminal venules, the release of catecholamine from adrenal medulla, and neurotransmission in the central nervous system. It has been associated with multiple processes, including memory and learning, circadian rhythm, and thermoregulation. It is also known to contribute to the pathophysiology of allergic diseases such as atopic dermatitis, asthma, anaphylaxis and allergic rhinitis. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jan 2015]

Synonyms

H1R; H1-R; HH1R; hisH1;

Bio Chemical Class

GPCR rhodopsin

Protein Sequence

MSLPNSSCLLEDKMCEGNKTTMASPQLMPLVVVLSTICLVTVGLNLLVLYAVRSERKLHTVGNLYIVSLSVADLIVGAVVMPMNILYLLMSKWSLGRPLCLFWLSMDYVASTASIFSVFILCIDRYRSVQQPLRYLKYRTKTRASATILGAWFLSFLWVIPILGWNHFMQQTSVRREDKCETDFYDVTWFKVMTAIINFYLPTLLMLWFYAKIYKAVRQHCQHRELINRSLPSFSEIKLRPENPKGDAKKPGKESPWEVLKRKPKDAGGGSVLKSPSQTPKEMKSPVVFSQEDDREVDKLYCFPLDIVHMQAAAEGSSRDYVAVNRSHGQLKTDEQGLNTHGASEISEDQMLGDSQSFSRTDSDTTTETAPGKGKLRSGSNTGLDYIKFTWKRLRSHSRQYVSGLHMNRERKAAKQLGFIMAAFILCWIPYFIFFMVIAFCKNCCNEHLHMFTIWLGYINSTLNPLIYPLCNENFKKTFKRILHIRS

Open

Disease

Allergic/hypersensitivity disorder, Alzheimer disease, Anxiety disorder, Asthma, Attention deficit hyperactivity disorder, Bipolar disorder, Breathing abnormality, Conjunctiva disorder, Corneal disease, Cough, Depression, Episodic vestibular syndrome, Headache, Insomnia, Morning sickness disorder, Nasopharyngitis, Nausea/vomiting, Obesity, Pain, Parkinsonism, Pruritus, Respiratory system disease, Rheumatoid arthritis, Schizophrenia, Sleep-wake disorder, Vasomotor/allergic rhinitis

Approved Drug

54 +

Clinical Trial Drug

10 +

Discontinued Drug

12 +

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Detailed Information

Histamine receptor H1 (HRH1) is an integral membrane protein belonging to the G protein-coupled receptor family. As a ubiquitous messenger molecule, histamine executes its biological effects through four subtypes of G-protein coupled receptors, with HRH1 being the first identified for clinical applications. These pathways induce cellular processes that contribute to both physiological and pathological conditions.

Extensive studies have been conducted on the typical function of HRH1 in allergic responses.It mediates the contraction of smooth muscles and regulates capillary permeability through the contraction of terminal venules. In the central nervous system, HRH1 influences neurotransmission, affecting processes such as memory formation, learning capabilities, and circadian rhythm regulation. The receptor's activation triggers Galphaq/11-protein signaling pathways, leading to cellular responses that contribute to both normal physiological functions and pathological conditions.

The traditional role of HRH1 in allergic responses has been extensively studied. It serves as a primary mediator in allergic diseases such as atopic dermatitis, asthma, anaphylaxis, and allergic rhinitis. This understanding has led to the development of various antihistamine medications, particularly H1 receptor antagonists, which have become cornerstone treatments for allergic conditions.

HRH1's Role in Cancer Microenvironment

Recent findings indicate that HRH1 is pivotal in the tumor microenvironment, mostly due to its elevated expression in tumor-associated macrophages (TAMs). Although cancer cells do not express HRH1, they are the primary contributors to elevated histamine levels in patient samples, complicating the tumor microenvironment significantly. The discovery of this chemical has resulted in novel approaches to cancer defense and potential therapies.

Numerous intricate mechanisms exist by which HRH1 and cancer defense interact. The concentration of HRH1 is significantly associated with indicators of T cell dysfunction and poor outcomes after treatment with checkpoint inhibitors. The receptor is mostly located in M2-type macrophages, which primarily function to inhibit the immune system's assault on malignancy. Researchers see significant alterations in the tumor microenvironment with the inhibition of HRH1, either by gene deletion or antihistamine treatment. The capacity of TAMs to inhibit the immune system diminishes, resulting in increased activity of T cells.

HRH1 combats cancer mostly by interacting with VISTA, an acronym for V-domain Ig inhibitor of T cell activation. Research indicates that inhibiting HRH1 activity significantly reduces VISTA mRNA levels in macrophages. This reduction induces alterations in several gene expressions, facilitating the transition of TAMs from the immune-suppressive M2 phenotype to the pro-inflammatory M1 phenotype. HRH1 regulates the positioning of the VISTA membrane via modulating calcium flux. This subsequently influences T cell functionality and tumor proliferation.

Figure 1: Histamine binding to HRH1 on macrophages promotes M2 polarization and VISTA membrane localization while blocking HRH1 shifts macrophages to M1, enhancing CD8+ T cell function and inhibiting tumor growth. Figure 1. The impact of Histamine binding to macrophages HRH1 on the tumor microenvironment. (Bai Z, et al., 2022)

Clinical Implications and Future Directions

Investigations concerning HRH1 used in clinical environments have shown favorable outcomes. Studies demonstrate that patients receiving HRH1-specific antihistamines during immune checkpoint blockade (ICB) treatment show significantly improved clinical outcomes. This finding has important implications for cancer treatment strategies, particularly in combining traditional immunotherapy with antihistamine treatments.

Plasma histamine levels have emerged as a potential predictor of treatment response. Clinical research indicates that patients with lower plasma histamine levels demonstrate higher overall response rates and better disease control when treated with anti-PD-1 therapy. This discovery suggests the possibility of using histamine levels as a biomarker for predicting immunotherapy effectiveness.

The intersection of allergic conditions and cancer treatment presents another crucial consideration. Research shows that allergic reactions, which release substantial amounts of histamine, may impair anti-tumor immunity and induce resistance to immunotherapy through the histamine-HRH1 axis. This finding highlights the importance of considering patients' allergy status when planning immunotherapy treatments.

Ongoing research endeavors concentrate on several critical domains. The exact ways that HRH1 transmission affects macrophage orientation are still being studied by scientists. They are also looking into other immune effectors that are controlled by antihistamines because using antihistamines along with immune checkpoint inhibitors gives better results against tumors than using anti-VISTA antibodies along with checkpoint inhibitors.

The advancing comprehension of HRH1's function in cancer therapy signifies a notable transition from its conventional link to allergy treatment. This evolution opens new possibilities for improving cancer treatment outcomes, particularly through strategic combinations of antihistamines with existing immunotherapy approaches.

References:

Li J, Chen W, Peng C, et al. Human H1 receptor (HRH1) gene polymorphism is associated with the severity of side effects after desloratadine treatment in Chinese patients with chronic spontaneous uticaria. Pharmacogenomics J. 2020;20(1):87-93.
Bai Z, Ai J, Wei X. Histamine and histamine receptor H1 (HRH1) axis: new target for enhancing immunotherapy response. Mol Biomed. 2022;3(1):11.

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