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Special Issue "Molecular Biology of Histamine Systems"

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: 31 December 2021.

Special Issue Editors

Prof. Dr. Paul Chazot
E-Mail Website
Guest Editor
Department of Biosciences, Durham University, Durham DH13LE, UK
Interests: ER stress; oxidative stress; inflammation; senescence; autophagy; proteinopathies; metallopathies; channelopathies; chronic; neuroglia; vascular
Dr. Ilona Obara
E-Mail Website
Guest Editor
Senior Lecturer of Pharmacology, School of Pharmacy, Institute of Neuroscience, University of Newcastle, UK

Special Issue Information

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.

Prof. Dr. Paul Chazot
Guest Editor

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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 (6 papers)

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Research

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Article
Specific Engineered G Protein Coupling to Histamine Receptors Revealed from Cellular Assay Experiments and Accelerated Molecular Dynamics Simulations
Int. J. Mol. Sci. 2021, 22(18), 10047; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221810047 - 17 Sep 2021
Cited by 1 | Viewed by 433
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 [...] Read more.
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, Emax) 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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Article
Label-Free Investigations on the G Protein Dependent Signaling Pathways of Histamine Receptors
Int. J. Mol. Sci. 2021, 22(18), 9739; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189739 - 09 Sep 2021
Cited by 1 | Viewed by 936
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) [...] Read more.
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 H1–4Rs 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 Gαq/11, Gαs, Gα12/13 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 hH1–4Rs occurred mainly, but not exclusively, via their canonical Gα proteins. For example, in addition to Gαi/o, the Gαq/11 protein was proven to contribute to the DMR response of hH3,4Rs. Moreover, the Gα12/13 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 H1–4Rs. Full article
(This article belongs to the Special Issue Molecular Biology of Histamine Systems)
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Article
Analysis of Missense Variants in the Human Histamine Receptor Family Reveals Increased Constitutive Activity of E4106.30×30K Variant in the Histamine H1 Receptor
Int. J. Mol. Sci. 2021, 22(7), 3702; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073702 - 02 Apr 2021
Viewed by 592
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. [...] Read more.
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 R1273.52×52H, R13934.57×57H, R4096.29×29H, and E4106.30×30K, 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 E4106.30×30K missense variant displays higher constitutive activity in G protein signaling as compared to wild-type H1R, whereas the opposite was observed for R1273.52×52H, R13934.57×57H, and R4096.29×29H. The E4106.30×30K 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 E4106.30×30K 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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Communication
Molecular Determinants of the Kinetic Binding Properties of Antihistamines at the Histamine H1 Receptors
Int. J. Mol. Sci. 2021, 22(5), 2400; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052400 - 27 Feb 2021
Viewed by 744
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 (kon and koff, respectively) of antihistamines have suggested that second-generation antihistamines have [...] Read more.
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 (kon and koff, respectively) of antihistamines have suggested that second-generation antihistamines have a long duration of action owing to the long residence time (1/koff) 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 koff values, there was no significant relationship with the kon values. QSAR analyses indicated that kon and koff 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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Article
Differential Regulation of Bilastine Affinity for Human Histamine H1 Receptors by Lys 179 and Lys 191 via Its Binding Enthalpy and Entropy
Int. J. Mol. Sci. 2021, 22(4), 1655; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041655 - 06 Feb 2021
Viewed by 659
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 Lys179ECL2 and [...] Read more.
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 Lys179ECL2 and Lys1915.39 of human H1 receptors might contribute to increased affinity of these antihistamines to H1 receptors. In this study, we evaluated the roles of Lys179ECL2 and Lys1915.39 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 Lys179ECL2 or Lys1915.39 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 Lys179ECL2 and Lys1915.39 to alanine reduced the affinity of bilastine to H1 receptors by reducing enthalpy- and entropy-dependent binding forces, respectively. These results suggest that Lys179ECL2 and Lys1915.39 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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Review
The Function of the Histamine H4 Receptor in Inflammatory and Inflammation-Associated Diseases of the Gut
Int. J. Mol. Sci. 2021, 22(11), 6116; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116116 - 06 Jun 2021
Cited by 1 | Viewed by 881
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 [...] Read more.
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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