The histamine H4 receptor as a new therapeutic target for inflammation

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Following the sequencing of the human genome, data-mining efforts have revealed the existence of a new histamine receptor that is expressed at high levels in mast cells and leukocytes. The histamine H4 receptor has a distinct pharmacological profile and the first compounds that act selectively on the H4 receptor have been developed. Initial experiments in vivo with H4 receptor antagonists indicate a role for the H4 receptor in inflammatory conditions.

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And then there were four…

Until 2000 histamine was thought to act via three G-protein-coupled receptors (GPCRs). The existence of these three histamine receptors (H1, H2 and H3) has been known since 1983, based on the activities of several pharmacological tools [1]; since then, these receptors have attracted considerable interest as therapeutic targets. Antagonists of either the H1 receptor [e.g. fexofenadine (Allegra®) and l-cetirizine (Xyzal®)] or the H2 receptor [e.g. cimetidine (Tagamet®) and ranitidine (Zantac®)]

The histamine H4 receptor protein

Extensive alternative splicing of the H3 receptor gene results in many H3 receptor isoforms that have differential signalling properties and tissue-expression profiles 4, 13. Although no reports of H4 receptor isoforms have been published, the similarity between the organization of the gene that encodes the H4 receptor and the gene that encodes the H3 receptor in humans [11] indicates that several H4 receptor isoforms might exist.

In the reported 390-amino-acid sequence of the human H4 receptor,

Signal transduction

The H4 receptor is coupled mainly to Gi/o proteins (Figure 2). In either stably or transiently transfected cells, H4 receptor activation leads to a pertussis-toxin-sensitive decrease in the forskolin-induced production of cAMP and the inhibition of downstream events such as cAMP responsive element-binding protein (CREB)-dependent gene transcription 5, 6, 7, 10. In addition, in stably transfected HEK-293 cells, H4 receptor stimulation results in the pertussis-toxin-sensitive activation of

The quest for selective H4 receptor ligands

Considering the high sequence similarity with the H3 receptor it is not surprising that the H4 receptor is activated by several H3 receptor agonists, including immepip (H4 receptor, Ki=9 nM) [10], imetit (H4 receptor, Ki=5 nM) [8] and (R)-α-methylhistamine (H4 receptor, Ki=146 nM) [32]. Furthermore, the H4 receptor is activated by the H2–H3 receptor antagonist burimamide (H4 receptor, Ki=180 nM) [32] and the H3 receptor antagonist clobenpropit (H4 receptor, Ki=13 nM) [18]. Thioperamide, an inverse

Expression of the H4 receptor

It has been difficult to identify conclusively which cell types express the H4 receptor because this receptor is expressed at low levels in most tissues. Furthermore, expression seems to be controlled by inflammatory stimuli 9, 12. These factors create problems when using reverse transcriptase polymerase chain reaction (RT–PCR) to study expression in primary cells because cell purity and the state of the cell will affect the results. As a further complication, antibodies to detect the presence

Function of the H4 receptor in primary cells

The presence of the H4 receptor on eosinophils has been confirmed by functional activity. In 1975 Clark et al. [49] observed that low concentrations of histamine induce eosinophil chemotaxis, which is now known to be mediated by the H4 receptor. Histamine also induces chemotaxis of eosinophils and this effect can be inhibited by H4 receptor antagonists 11, 31. In addition to acting as a chemoattractant, histamine enhances the chemotaxis induced by eotaxin and macrophage chemoattractant protein

The role of the H4 receptor in vivo

The function of the H4 receptor in mast cells, eosinophils and T cells implies that it has a role in inflammatory and immune responses 52, 53, 54. One of the most important functions of histamine in an inflammatory response is to increase vascular permeability, but the H4 receptor has no role in this response in vivo. This is not surprising because this effect is mediated by the H1 receptor [40]. However, other anti-inflammatory effects of H4 receptor antagonists in vivo have been reported. H4

Concluding remarks

Information from the human genome has been used to identify the H4 receptor, which is an addition to the histamine receptor family and a possible new target for drugs. The relatively selective expression of the H4 receptor on hematopoietic cells and the H4 receptor effects on cellular function indicate that H4 receptors have a role in mediating either immune or inflammatory responses. The recent development of selective ligands for the H4 receptor has enabled the elucidation of receptor

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