Review
Molecular and cellular analysis of human histamine receptor subtypes

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The human histamine receptors hH1R and hH2R constitute important drug targets, and hH3R and hH4R have substantial potential in this area. Considering the species-specificity of pharmacology of HxR orthologs, it is important to analyze hHxRs. Here, we summarize current knowledge of hHxRs endogenously expressed in human cells and hHxRs recombinantly expressed in mammalian and insect cells. We present the advantages and disadvantages of the various systems. We also discuss problems associated with the use of hHxR antibodies, an issue of general relevance for G-protein-coupled receptors (GPCRs). There is much greater overlap in activity of ‘selective’ ligands for other hHxRs than the cognate receptor subtype than generally appreciated. Studies with native and recombinant systems support the concept of ligand-specific receptor conformations, encompassing agonists and antagonists. It is emerging that for characterization of hHxR ligands, one cannot rely on a single test system and a single parameter. Rather, multiple systems and parameters have to be studied. Although such studies are time-consuming and expensive, ultimately, they will increase drug safety and efficacy.

Highlights

► This review provides a comprehensive summary of our knowledge on human histamine receptors. ► We critically discuss the limitations of currently available ligands. ► We highlight pitfalls associated with the use of histamine receptor antibodies ► We provide constructive suggestions for future research in the field.

Section snippets

Clinical relevance of drugs targeting human histamine receptors

Histamine plays an important role in diverse human diseases. In immediate-type (type I) allergies, massive IgE-triggered release of histamine from mast cells takes place; this results in activation of the H1 receptor (H1R) and contributes to the development of conjunctivitis and rhinitis with the lead symptoms pruritus (itching), erythema (reddening of the skin), and edema (accumulation of fluid in the skin) 1, 2. Accordingly, H1R antagonists, specifically compounds of the second generation

Challenges to the analysis of hHxR subtypes in native human cells: the H1 receptor

From an experimental point of view, it is not easy to comprehensively characterize HxR ligands in human cells endogenously expressing hHxRs. Table 1 summarizes the results of selected studies dealing with the characterization of hHxRs in native human cells and critically analyzes these studies. We list several classic studies in the field, but clearly focus on the most recent data. Papers comprise studies on pharmacology, signal transduction, cell biology, and clinical relevance of hHxRs. We

Analysis of the H2 receptor in human cells

Among all hHxRs, hH2R is the GPCR that can be studied most readily in human cells. Functionally, human neutrophils express H2R but not H4R, although at the mRNA level, H4R is present 11, 12, 17, 32. The closely related eosinophils express both functional H2R and H4R [33]. Neutrophils can be easily obtained in large numbers from peripheral blood and from buffy coat preparations. Hence, in these cells, H2R has been analyzed in considerable detail. In neutrophils and eosinophils, H2R mediates

Analysis of the H3 receptor in human cells: an elusive goal

H3R is a receptor exclusively expressed in neurons 43, 44, and to the best of our knowledge there is currently no human cell culture model that expresses hH3R endogenously at sufficient levels to allow for detailed pharmacological studies. To circumvent these methodological problems, hH3R has to be expressed in mammalian or insect cell expression systems. Studies on hH3R in mammalian expression systems have been reviewed elsewhere 8, 20. The pharmacological properties of representative hHxR

The human H4 receptor can be studied in eosinophils, but it is a difficult task

The best-studied human cell type expressing H4R is the eosinophil. Several independent groups have consistently reported on the functional expression of H4R in human eosinophils 33, 45, 46, 47, 48. H4R mediates increases in [Ca2+]i and a very moderate activation of chemotaxis but no activation of O2 formation or release of cytotoxic enzymes. Thus, in contrast to other typical eosinophil GPCRs such as the eotaxin receptor and formyl peptide receptor, hH4R mediates only incomplete eosinophil

Analysis of hHxR subtypes in mammalian expression systems

Based on the limitations of hHxR analysis in native human cells, recombinant systems are essential for comprehensive hHxR characterization. hHxRs have been expressed in classic mammalian expression systems, including HEK293 cells, CHO cells, NIH-3T3 cells, and COS-7 cells (Table 2) 57, 58, 59, 60, 61. hH3R and hH4R have also been expressed in SK-N-MC cells (Table 2) [55]. In most studies, only one particular hHxR was studied, and there are only a limited number of studies in which several or

Analysis of human histamine receptor subtypes in Spodoptera frugiperda Sf9 insect cells

In Sf9 cells, all hHxRs were functionally reconstituted with G proteins, and unlike in mammalian expression systems, all hHxRs could be studied using one and the same parameter, namely high-affinity GTPase activity. Table 3 summarizes the most important properties of hHxR expression systems in Sf9 insect cells, and Table 4 summarizes the results of the pharmacological analysis of representative hHxR ligands in this system. This analysis reveals that, despite intense research in this field for

Overlap in interaction of ligands with human histamine receptor subtypes

As was already observed for native H1R and H2R in guinea pig organs [77], arpromidine and related imidazolylpropylguanidines bearing an H1R antagonist-derived moiety at the guanidine group instead of the cimetidine-like portion of impromidine are dual hH1R antagonists/hH2R agonists 28, 74 (Figure 1 and Table 4). Such a pharmacological profile may actually be clinically useful because H2R activation results in anti-inflammatory effects (Table 1). Hence, dual H1R antagonists/H2R agonists could be

Comparison of hHxR ligand binding sites

Figure 2 shows an alignment of transmembrane (TM) regions and extracellular loops (ECLs) of hHxRs and hHxR models docked with selected ligands from Figure 1. The alignment and phylogenetic trees indicate that hHxRs are rather distantly related, with only H3R and H4R showing a high degree of sequence similarity. Nevertheless, the binding sites of all hHxRs are structurally and spatially similar, leading to overlaps in ligand interactions and complicating the design of selective agonists and

Functional selectivity of agonists and antagonists

The pharmacological profile of hH2R in terms of agonist potencies and efficacies is almost identical when the receptor is coupled to the long and short splice variants of Gsα [75]. However, when hH2R coupling to insect cell Gs is studied measuring adenylyl cyclase activity as parameter, the pharmacological profile is different from the profile of hH2R coupled to mammalian Gs proteins, indicating that the various hH2R conformations differ in their ability to couple to mammalian and insect cell Gs

Unresolved questions and future studies

Both hH3R and hH4R exhibit high constitutive activity when expressed in Sf9 cells 65, 66. Na+ acts as an allosteric inverse agonist at hH3R and reduces constitutive hH3R activity [98]. The structural basis of allosteric modulation of GPCRs by Na+ has been resolved recently, (i.e., interaction of Na+ with a highly conserved aspartate residue in the second transmembrane domain plays a critical role [99]). In marked contrast to hH3R [98], the constitutive activity of hH4R is resistant to

Concluding remarks

All four hHxRs constitute established or promising drug targets, particularly for antagonists, and to a much more limited extent, for agonists. Human cell systems endogenously expressing hH1R, hH2R, and hH4R but not hH3R are available. Mammalian and insect cell expression systems exist for all hH4Rs. In Sf9 cells, hHxR ligands can be assessed using the same parameter for all hHxRs, namely high-affinity GTPase activity. There is substantial overlap in the interactions of various chemical ligand

Acknowledgments

R.S. is most grateful to Dr Brian Kobilka (Stanford University, CA, USA) for providing him the privilege to obtain postdoctoral training in his laboratory from 1995 to 1998. We acknowledge the collaboration with Drs H. Appl, S. Beermann, G. Bernhardt, T. Birnkammer, I. Brunskole, R. Burde, H. Burhenne, K. Burleigh, T. Bürckstümmer, K-F. Deml, S. Elz, R. Geyer, P. Ghorai, L. Grünbaum, P. Igel, A. Höer, T. Holzammer, M.T. Kelley, T. Kottke, A. Kraus, M. Kunze, D. Neumann, D. Papa, H. Preuss, T.M.

Glossary

Anti-peptide antibody
antibody, which is generated by immunization of the host organism with a peptide, usually conjugated to a larger carrier protein such as keyhole limpet hemocyanin.
Epitope
also known as antigen determinant, part of an antigen, which is recognized by molecules of the immune system.
Fc receptor
receptor that recognizes the Fc part of the heavy chain of an antibody.
Monoclonal antibody (mAb)
preparations of antibodies with identical epitope-directed specificity because all

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