Abstract
The histamine H4 receptor (H4R) was first noted as a sequence in genomic databases that had features of a class A G-protein coupled receptor. This putative receptor was found to bind histamine consistent with its homology to other histamine receptors and thus became the fourth member of the histamine receptor family. Due to the previous success of drugs that target the H1 and H2 receptors, an effort was made to understand the function of this new receptor and determine if it represented a viable drug target. Taking advantage of the vast literature on the function of histamine, a search for histamine activity that did not appear to be mediated by the other three histamine receptors was undertaken. From this asthma and pruritus emerged as areas of particular interest. Histamine has long been suspected to play a role in the pathogenesis of asthma, but antihistamines that target the H1 and H2 receptors have not been shown to be effective for this condition. The use of selective ligands in animal models of asthma has now potentially filled this gap by showing a role for the H4R in mediating lung function and inflammation. A similar story exists for chronic pruritus associated with conditions such as atopic dermatitis. Antihistamines that target the H1 receptor are effective in reducing acute pruritus, but are ineffective in pruritus experienced by patients with atopic dermatitis. As for asthma, animal models have now suggested a role for the H4R in mediating pruritic responses, with antagonists of the H4R reducing pruritus in a number of different conditions. The anti-pruritic effect of H4R antagonists has recently been shown in human clinical studies, validating the preclinical findings in the animal models. A selective H4R antagonist inhibited histamine-induced pruritus in health volunteers and reduced pruritus in patients with atopic dermatitis. The history to date of the H4R provides an excellent example of the deorphanization of a novel receptor and the translation of this into clinical efficacy in humans.
Highlights
There are four known G-coupled protein receptors (GPCRs) that use histamine as a ligand
At doses and time points where the concentration of JNJ 39758979 was above 100 nM, a statistically significant inhibition was observed. This level of potency was similar to what when the compound was added to blood in vitro (Thurmond et al, 2014a). These results show that in vivo administration of an H4 receptor (H4R) antagonist in humans can have impact on eosinophil function
In vivo H4R antagonist can inhibit LPS induced production of inflammatory cytokines and this is reduced in H4R-deficient mice (Cowden et al, 2013). This link between toll-like receptors (TLRs) and H4R may important driving asthmatic responses since it has been shown that H4R antagonists are only effective in mouse asthma models when LPS is present (Cowden et al, 2013)
Summary
There are four known G-coupled protein receptors (GPCRs) that use histamine as a ligand. The breakthrough came using a different approach where sequences were identified that contained general homologies to GPCR (e.g., predicted seven transmembrane domains and other common residues) These putative orphan GPCR genes were screened for binding to likely ligands. Using such an approach, a novel sequence was discovered that encoded a GPCR that bound to histamine and had pharmacology that matched that described for the H3R (Lovenberg et al, 1999). The discovery of the gene for the H3R provided a tool for additional homology searches of databases for related sequences This yielded a putative receptor that was ∼35% identical to the H3R and when expressed in heterologous systems was found to have a high affinity for histamine (Liu et al, 2001). One hint of function was evident from the expression pattern described in the original cloning papers that showed a fairly selective expression on bone marrow and hematopoietic cells known to be involved in inflammatory and immune responses
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