Molecular and biochemical pharmacology of the histamine H4 receptor

Abstract

The elucidation of the human genome has had a major impact on histamine receptor research. The identification of the human H4 receptor by several groups has been instrumental for a new appreciation of the role of histamine in the modulation of immune function. In this review, we summarize the historical developments and the molecular and biochemical pharmacology of the H4 receptor.

Figure 1

Snake plot of the human histamine H₄ receptor. The full-length receptor consists of 390 amino acids, which form seven transmembrane helices, three extracellular loops and three intracellular loops, with an extracellular N-terminal and an intracellular C-terminal peptide; the dotted line represents the putative disulfide bridge that links the cysteines in the third transmembrane and second extracellular loop. Residues Asp^3.32 and Glu^5.46 that play important roles in histamine binding are marked with bold border. The H₄R₆₇ isoform only contains the first 67 N-terminal residues (marked in white), while the H₄R₃₀₂ lacks the residues marked in grey. The conserved residues in the family A of G protein-coupled receptors are depicted in black circles, while the putative glycosylation sites (Asn⁵ and Asn⁹) are indicated with arrows. A potential palmitoylation site (Cys³⁷⁴) at the C-terminal tail is suggested to be close to the membrane following membrane insertion of a putative attached palmitic acid.

Figure 2

Schematic representation of a homology model of the human histamine H₄ receptor. The figure shows the seven transmembrane domains and the position of the ligand binding site. In the box details of the histamine binding site, as determined using ab initio calculations is shown (reproduced with permission from Jongejan et al., 2008).

Figure 3

Phylogenetic tree of H₄ receptor orthologues. The sequences are obtained from http://www.ensembl.org and the phylogram was created with ClustalW.

Figure 4

Anti-hH_4(374–390) receptor antibody reacts with human H₄ receptor protein in spleen tissue lysate and sections. (A) Immunoblot of human spleen lysate (10 µg). Anti-H_4(374–390) antibodies were used at 2 µg·mL⁻¹, incubated overnight at 4°C and developed as described in van Rijn et al. (2006). In addition to the putative monomer at M_w 31 kDa, two higher molecular weight species were detected at 59 and 66 kDa. (B) Immunostaining of human spleen slice (bar = 50 µm) using anti-H_4(374–390) at 1 µg·mL⁻¹ using an immunohistochemical protocol described in Chazot et al. (2001).

Figure 5

First and second generation H₄ receptor agonists with different selectivity profiles.

Figure 6

First and second generation H₄ receptor antagonists. Except for thioperamide (10) the antagonists display at least a 100-fold selectivity for the histamine H₄ receptor over the histamine H₃ receptor.