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Molecular Biology of Histamine Systems

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 29772

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Dr. Paul L. Chazot

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Department of Biosciences, Durham University, Durham DH1 3LE, UK
Interests: ER stress; oxidative stress; inflammation; senescence; autophagy; proteinopathies; metallopathies; channelopathies; chronic; neuroglia; vascular
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Dr. Ilona Obara

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Senior Lecturer of Pharmacology, School of Pharmacy, Institute of Neuroscience, University of Newcastle, Newcastle, UK
Interests: pharmacology
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Dear Colleagues,

Histamine is arguably the most pleiotropic transmitter in the human body. Despite over a century of study since the first seminal work of Sr Henry Dale, who first identified an action for histamine on living tissue, and with significant advances in histamine pharmacology and drug development, with successful drug targeting three of the four histamine receptors, H₁-₄R, we are still lacking in a full understanding of the molecular biology of the histamine system. Histamine is synthesized from the amino acid histidine via the enzyme, histadine decarboxylase (HDC). The histamine receptors are classic G-protein coupled receptors. Major pharmacological heterogeneity between and within species has hindered the clinical development of H₃ and H₄R-targeted drugs. The pharmacological heterogeneity displayed by the histamine receptors are thought in part to be a result of alternative splicing which generates a number of possible splice variants, some of which have been shown to be functional and others which appear to be non-functional in terms of ligand binding and signal transduction. mRNA encoding the different isoforms has been shown to be distributed throughout the central nervous system in a region specific manner, but their relevance is yet to be established. Genetic polymorphisms have also been identified within the human receptor and HDC genes, some have been linked to disease. Despite the importance of histamine, transcriptional regulation of histamine receptor and HDC gene expression in mammals is still poorly understood. Furthermore, there are significant deficits in our knowledge regarding native histamine signalling pathways. This themed volume will endeavour to extend our understanding of these important issues.

Dr. Paul L. Chazot
Dr. Ilona Obara
Guest Editors

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Keywords

Histamine
Molecular biology
Genetics
Mutations
Disease
Genomics
Histamine signalling
Synthesis
Metabolism
Isoforms
Splicing
Receptors
Gene regulation
Molecular structure
Microbiome

Published Papers (10 papers)

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Editorial

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2 pages, 186 KiB

Open AccessEditorial

Molecular Biology of Histamine System, Volume 1

by Paul Chazot

Int. J. Mol. Sci. 2022, 23(9), 5026; https://doi.org/10.3390/ijms23095026 - 30 Apr 2022

Viewed by 1243

Abstract

Histamine is arguably the most pleiotropic transmitted in the human body [...] Full article

(This article belongs to the Special Issue Molecular Biology of Histamine Systems)

Research

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20 pages, 2837 KiB

Open AccessArticle

Histaminergic System and Inflammation-Related Genes in Normal Large Intestine and Adenocarcinoma Tissues: Transcriptional Profiles and Relations

by Grażyna Janikowska, Tomasz Janikowski, Marta Plato, Urszula Mazurek, Joanna Orchel, Mieszko Opiłka and Zbigniew Lorenc

Int. J. Mol. Sci. 2023, 24(5), 4913; https://doi.org/10.3390/ijms24054913 - 03 Mar 2023

Cited by 1 | Viewed by 1449

Abstract

Transcriptional analyses such as microarray data have contributed to the progress in the diagnostics and therapy of colorectal cancer (CRC). The need for such research is still present because of the disease being common in both men and women with a high second position in cancer rankings. Little is known about the relations between the histaminergic system and inflammation in the large intestine and CRC. Therefore, the aim of this study was to evaluate the expression of genes related to the histaminergic system and inflammation in the CRC tissues at three cancer development designs: all tested CRC samples, low (LCS) and high (HCS) clinical stage, and four clinical stages (CSI–CSIV), to the control. The research was carried out at the transcriptomic level, analysing hundreds of mRNAs from microarrays, as well as carrying out RT-PCR analysis of histaminergic receptors. The following histaminergic mRNAs: GNA15, MAOA, WASF2A, and inflammation-related: AEBP1, CXCL1, CXCL2, CXCL3, CXCL8, SPHK1, TNFAIP6, were distinguished. Among all analysed transcripts, AEBP1 can be considered the most promising diagnostic marker in the early stage of CRC. The results showed 59 correlations between differentiating genes of the histaminergic system and inflammation in the control, control and CRC, and CRC. The tests confirmed the presence of all histamine receptor transcripts in both the control and colorectal adenocarcinoma. Significant differences in expression were stated for HRH2 and HRH3 in the advanced stages of CRC adenocarcinoma. The relations between the histaminergic system and inflammation-linked genes in both the control and the CRC have been observed. Full article

(This article belongs to the Special Issue Molecular Biology of Histamine Systems)

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15 pages, 2389 KiB

Open AccessArticle

Histamine H4 Receptor Agonism Induces Antitumor Effects in Human T-Cell Lymphoma

by Mariángeles Clauzure, Mónica A. Táquez Delgado, Jude M. Phillip, Maria V. Revuelta, Leandro Cerchietti and Vanina A. Medina

Int. J. Mol. Sci. 2022, 23(3), 1378; https://doi.org/10.3390/ijms23031378 - 26 Jan 2022

Cited by 5 | Viewed by 2654

Abstract

The discovery of the human histamine H4 receptor (H4R) has contributed to our understanding of the role of histamine in numerous physiological and pathological conditions, including tumor development and progression. The lymph nodes of patients with malignant lymphomas have shown to contain high levels of histamine, however, less is known regarding the expression and function of the H4R in T-cell lymphoma (TCL). In this work we demonstrate the expression of H4R isoforms (mRNA and protein) in three human aggressive TCL (OCI-Ly12, Karpas 299, and HuT78). Histamine and specific H4R agonists (VUF8430 and JNJ28610244) significantly reduced cell viability in a dose-dependent manner (p < 0.05). The combined treatment with the H4R antagonist (JNJ7777120, 10 µM) reversed the effects of the H4R ligands. Importantly, we screened a drug repurposing library of 433 FDA-approved compounds (1 μM) in combination with histamine (10 μM) in Hut78 cells. Histamine produced a favorable antitumor effect with 18 of these compounds, including the histone deacetylase inhibitor panobinostat. Apoptosis, proliferation, and oxidative stress studies confirmed the antitumoral effects of the combination. We conclude that the H4R is expressed in TCL, and it is involved in histamine-mediated responses. Full article

(This article belongs to the Special Issue Molecular Biology of Histamine Systems)

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16 pages, 2584 KiB

Open AccessArticle

Histamine Increases Th2 Cytokine-Induced CCL18 Expression in Human M2 Macrophages

by Susanne Mommert, Judith Tabea Schaper, Katrin Schaper-Gerhardt, Ralf Gutzmer and Thomas Werfel

Int. J. Mol. Sci. 2021, 22(21), 11648; https://doi.org/10.3390/ijms222111648 - 28 Oct 2021

Cited by 12 | Viewed by 2429

Abstract

The chemokine CCL18 is produced in cells of the myelomonocytic lineage and represents one of the most highly expressed chemokines in lesional skin and serum of atopic dermatitis patients. We investigated the role of histamine in CCL18 production in human monocyte-derived M2 macrophages differentiated in the presence of M-CSF and activated with IL-4, IL-13 or with IL-10. Since expression and regulation of histamine H1 receptor (H1R), H2R and H4R by IL-4 and IL-13 on human M2 macrophages were described, we analyzed expression of the histamine receptors in response to IL-10 stimulation by quantitative RT-PCR. IL-10 upregulated H2R and downregulated H4R mRNA expression by trend in M2 macrophages. IL-10, but in a more pronounced manner, IL-4 and IL-13, also upregulated CCL18. Histamine increased the cytokine-induced upregulation of CCL18 mRNA expression by stimulating the H2R. This effect was stronger in IL-10-stimulated M2 macrophages where the upregulation of CCL18 was confirmed at the protein level by ELISA using selective histamine receptor agonist and antagonists. The histamine-induced CCL18 upregulation in IL-10-activated M2 macrophages was almost similar in cells obtained from atopic dermatitis patients compared to cells from healthy control persons. In summary, our data stress a new function of histamine showing upregulation of the Th2 cells attracting chemokine CCL18 in human, activated M2 macrophages. This may have an impact on the course of atopic dermatitis and for the development of new therapeutic interventions. Full article

(This article belongs to the Special Issue Molecular Biology of Histamine Systems)

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21 pages, 4381 KiB

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Specific Engineered G Protein Coupling to Histamine Receptors Revealed from Cellular Assay Experiments and Accelerated Molecular Dynamics Simulations

by Carina Höring, Marcus Conrad, Christian A. Söldner, Jinan Wang, Heinrich Sticht, Andrea Strasser and Yinglong Miao

Int. J. Mol. Sci. 2021, 22(18), 10047; https://doi.org/10.3390/ijms221810047 - 17 Sep 2021

Cited by 4 | Viewed by 3192

Abstract

G protein-coupled receptors (GPCRs) are targets of extracellular stimuli and hence occupy a key position in drug discovery. By specific and not yet fully elucidated coupling profiles with α subunits of distinct G protein families, they regulate cellular responses. The histamine H₂ and H₄ receptors (H₂R and H₄R) are prominent members of Gs- and Gi-coupled GPCRs. Nevertheless, promiscuous G protein and selective Gi signaling have been reported for the H₂R and H₄R, respectively, the molecular mechanism of which remained unclear. Using a combination of cellular experimental assays and Gaussian accelerated molecular dynamics (GaMD) simulations, we investigated the coupling profiles of the H₂R and H₄R to engineered mini-G proteins (mG). We obtained coupling profiles of the mGs, mGsi, or mGsq proteins to the H₂R and H₄R from the mini-G protein recruitment assays using HEK293T cells. Compared to H₂R–mGs expressing cells, histamine responses were weaker (pEC₅₀, E_max) for H₂R–mGsi and –mGsq. By contrast, the H₄R selectively bound to mGsi. Similarly, in all-atom GaMD simulations, we observed a preferential binding of H₂R to mGs and H₄R to mGsi revealed by the structural flexibility and free energy landscapes of the complexes. Although the mG α5 helices were consistently located within the HR binding cavity, alternative binding orientations were detected in the complexes. Due to the specific residue interactions, all mG α5 helices of the H₂R complexes adopted the Gs-like orientation toward the receptor transmembrane (TM) 6 domain, whereas in H₄R complexes, only mGsi was in the Gi-like orientation toward TM2, which was in agreement with Gs- and Gi-coupled GPCRs structures resolved by X-ray/cryo-EM. These cellular and molecular insights support (patho)physiological profiles of the histamine receptors, especially the hitherto little studied H₂R function in the brain, as well as of the pharmacological potential of H₄R selective drugs. Full article

(This article belongs to the Special Issue Molecular Biology of Histamine Systems)

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33 pages, 7432 KiB

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Label-Free Investigations on the G Protein Dependent Signaling Pathways of Histamine Receptors

by Ulla Seibel-Ehlert, Nicole Plank, Asuka Inoue, Guenther Bernhardt and Andrea Strasser

Int. J. Mol. Sci. 2021, 22(18), 9739; https://doi.org/10.3390/ijms22189739 - 09 Sep 2021

Cited by 8 | Viewed by 3975

Abstract

G protein activation represents an early key event in the complex GPCR signal transduction process and is usually studied by label-dependent methods targeting specific molecular events. However, the constrained environment of such “invasive” techniques could interfere with biological processes. Although histamine receptors (HRs) represent (evolving) drug targets, their signal transduction is not fully understood. To address this issue, we established a non-invasive dynamic mass redistribution (DMR) assay for the human H_1–4Rs expressed in HEK cells, showing excellent signal-to-background ratios above 100 for histamine (HIS) and higher than 24 for inverse agonists with pEC₅₀ values consistent with literature. Taking advantage of the integrative nature of the DMR assay, the involvement of endogenous Gα_q/11, Gα_s, Gα_12/13 and Gβγ proteins was explored, pursuing a two-pronged approach, namely that of classical pharmacology (G protein modulators) and that of molecular biology (Gα knock-out HEK cells). We showed that signal transduction of hH_1–4Rs occurred mainly, but not exclusively, via their canonical Gα proteins. For example, in addition to Gα_i/o, the Gα_q/11 protein was proven to contribute to the DMR response of hH_3,4Rs. Moreover, the Gα_12/13 was identified to be involved in the hH₂R mediated signaling pathway. These results are considered as a basis for future investigations on the (patho)physiological role and the pharmacological potential of H_1–4Rs. Full article

(This article belongs to the Special Issue Molecular Biology of Histamine Systems)

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15 pages, 12333 KiB

Open AccessArticle

Analysis of Missense Variants in the Human Histamine Receptor Family Reveals Increased Constitutive Activity of E410^6.30×30K Variant in the Histamine H₁ Receptor

by Xiaoyuan Ma, Marta Arimont Segura, Barbara Zarzycka, Henry F. Vischer and Rob Leurs

Int. J. Mol. Sci. 2021, 22(7), 3702; https://doi.org/10.3390/ijms22073702 - 02 Apr 2021

Cited by 4 | Viewed by 2080

Abstract

The Exome Aggregation Consortium has collected the protein-encoding DNA sequences of almost 61,000 unrelated humans. Analysis of this dataset for G protein-coupled receptor (GPCR) proteins (available at GPCRdb) revealed a total of 463 naturally occurring genetic missense variations in the histamine receptor family. In this research, we have analyzed the distribution of these missense variations in the four histamine receptor subtypes concerning structural segments and sites important for GPCR function. Four missense variants R127^3.52×52H, R139^34.57×57H, R409^6.29×29H, and E410^6.30×30K, were selected for the histamine H₁ receptor (H₁R) that were hypothesized to affect receptor activity by interfering with the interaction pattern of the highly conserved D(E)RY motif, the so-called ionic lock. The E410^6.30×30K missense variant displays higher constitutive activity in G protein signaling as compared to wild-type H₁R, whereas the opposite was observed for R127^3.52×52H, R139^34.57×57H, and R409^6.29×29H. The E410^6.30×30K missense variant displays a higher affinity for the endogenous agonist histamine than wild-type H₁R, whereas antagonist affinity was not affected. These data support the hypothesis that the E410^6.30×30K mutation shifts the equilibrium towards active conformations. The study of these selected missense variants gives additional insight into the structural basis of H₁R activation and, moreover, highlights that missense variants can result in pharmacologically different behavior as compared to wild-type receptors and should consequently be considered in the drug discovery process. Full article

(This article belongs to the Special Issue Molecular Biology of Histamine Systems)

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9 pages, 1404 KiB

Open AccessCommunication

Molecular Determinants of the Kinetic Binding Properties of Antihistamines at the Histamine H₁ Receptors

by Hayato Akimoto, Yoshihiro Uesawa and Shigeru Hishinuma

Int. J. Mol. Sci. 2021, 22(5), 2400; https://doi.org/10.3390/ijms22052400 - 27 Feb 2021

Cited by 3 | Viewed by 2456

Abstract

The binding affinity of ligands for their receptors is determined by their kinetic and thermodynamic binding properties. Kinetic analyses of the rate constants of association and dissociation (k_on and k_off, respectively) of antihistamines have suggested that second-generation antihistamines have a long duration of action owing to the long residence time (1/k_off) at the H₁ receptors. In this study, we examined the relationship between the kinetic and thermodynamic binding properties of antihistamines, followed by an evaluation of the structural determinants responsible for their kinetic binding properties using quantitative structure–activity relationship (QSAR) analyses. We found that whereas the binding enthalpy and entropy might contribute to the increase and decrease, respectively, in the k_off values, there was no significant relationship with the k_on values. QSAR analyses indicated that k_on and k_off values could be determined by the descriptors FASA_H (water-accessible surface area of all hydrophobic atoms divided by total water-accessible surface area) and vsurf_CW2 (a 3D molecular field descriptor weighted by capacity factor 2, the ratio of the hydrophilic surface to the total molecular surface), respectively. These findings provide further insight into the mechanisms by which the kinetic binding properties of antihistamines are regulated by their thermodynamic binding forces and physicochemical properties. Full article

(This article belongs to the Special Issue Molecular Biology of Histamine Systems)

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8 pages, 1531 KiB

Open AccessArticle

Differential Regulation of Bilastine Affinity for Human Histamine H₁ Receptors by Lys 179 and Lys 191 via Its Binding Enthalpy and Entropy

by Hayato Akimoto, Minoru Sugihara and Shigeru Hishinuma

Int. J. Mol. Sci. 2021, 22(4), 1655; https://doi.org/10.3390/ijms22041655 - 06 Feb 2021

Cited by 2 | Viewed by 2213

Abstract

Bilastine, a zwitterionic second-generation antihistamine containing a carboxyl group, has higher selectivity for H₁ receptors than first-generation antihistamines. Ligand-receptor docking simulations have suggested that the electrostatic interaction between the carboxyl group of second-generation antihistamines and the amino group of Lys179^ECL2 and Lys191^5.39 of human H₁ receptors might contribute to increased affinity of these antihistamines to H₁ receptors. In this study, we evaluated the roles of Lys179^ECL2 and Lys191^5.39 in regulating the electrostatic and hydrophobic binding of bilastine to H₁ receptors by thermodynamic analyses. The binding enthalpy and entropy of bilastine were estimated from the van ’t Hoff equation using the dissociation constants. These constants were obtained from the displacement curves against the binding of [³H] mepyramine to membrane preparations of Chinese hamster ovary cells expressing wild-type human H₁ receptors and their Lys179^ECL2 or Lys191^5.39 mutants to alanine at various temperatures. We found that the binding of bilastine to wild-type H₁ receptors occurred by enthalpy-dependent binding forces and, more dominantly, entropy-dependent binding forces. The mutation of Lys179^ECL2 and Lys191^5.39 to alanine reduced the affinity of bilastine to H₁ receptors by reducing enthalpy- and entropy-dependent binding forces, respectively. These results suggest that Lys179^ECL2 and Lys191^5.39 differentially contribute to the increased binding affinity to bilastine via electrostatic and hydrophobic binding forces. Full article

(This article belongs to the Special Issue Molecular Biology of Histamine Systems)

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Review

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17 pages, 846 KiB

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The Function of the Histamine H4 Receptor in Inflammatory and Inflammation-Associated Diseases of the Gut

by Bastian Schirmer and Detlef Neumann

Int. J. Mol. Sci. 2021, 22(11), 6116; https://doi.org/10.3390/ijms22116116 - 06 Jun 2021

Cited by 17 | Viewed by 5817

Abstract

Histamine is a pleiotropic mediator involved in a broad spectrum of (patho)-physiological processes, one of which is the regulation of inflammation. Compounds acting on three out of the four known histamine receptors are approved for clinical use. These approved compounds comprise histamine H1-receptor (H₁R) antagonists, which are used to control allergic inflammation, antagonists at H₂R, which therapeutically decrease gastric acid release, and an antagonist at H₃R, which is indicated to treat narcolepsy. Ligands at H₄R are still being tested pre-clinically and in clinical trials of inflammatory diseases, including rheumatoid arthritis, asthma, dermatitis, and psoriasis. These trials, however, documented only moderate beneficial effects of H₄R ligands so far. Nevertheless, pre-clinically, H₄R still is subject of ongoing research, analyzing various inflammatory, allergic, and autoimmune diseases. During inflammatory reactions in gut tissues, histamine concentrations rise in affected areas, indicating its possible biological effect. Indeed, in histamine-deficient mice experimentally induced inflammation of the gut is reduced in comparison to that in histamine-competent mice. However, antagonists at H₁R, H₂R, and H₃R do not provide an effect on inflammation, supporting the idea that H₄R is responsible for the histamine effects. In the present review, we discuss the involvement of histamine and H₄R in inflammatory and inflammation-associated diseases of the gut. Full article

(This article belongs to the Special Issue Molecular Biology of Histamine Systems)

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