Expression and functional properties of canine, rat, and murine histamine H4 receptors in Sf9 insect cells

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 2011-05, Vol.383 (5), p.457-470
• Main Authors: Schnell, David, Brunskole, Irena, Ladova, Katerina, Schneider, Erich H., Igel, Patrick, Dove, Stefan, Buschauer, Armin, Seifert, Roland
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Biomedical and Life Sciences; Biomedicine; Cell Line; Dogs; Histamine - metabolism; Humans; Insecta; Mice; Molecular Sequence Data; Neurosciences; Original Article; Pharmacology/Toxicology; Protein Binding; Radioligand Assay; Rats; Receptors, G-Protein-Coupled - biosynthesis; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - physiology; Receptors, Histamine - biosynthesis; Receptors, Histamine - chemistry; Receptors, Histamine - physiology; Receptors, Histamine H4; Species Specificity
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-011-0612-3

The histamine H 4 receptor (H 4 R) is expressed on cells of the immune system including eosinophils, dendritic cells, and T cells and plays an important role in the pathogenesis of bronchial asthma, atopic dermatitis, and pruritus. Analysis of the H 4 R in these diseases depends on the use of animal models. However, there are substantial pharmacological differences between various H 4 R species orthologs. The purpose of this study was to analyze the pharmacological properties of canine, rat, and murine H 4 R in comparison to human H 4 R expressed in Sf9 insect cells. Only hH 4 R and cH 4 R exhibited a sufficiently high [ 3 H]histamine affinity for radioligand binding studies. Generally, cH 4 R exhibited lower ligand-affinities than hH 4 R. Similarly, in high-affinity GTPase studies, ligands were more potent at hH 4 R than at other H 4 R species orthologs. Unlike the other H 4 R species orthologs, hH 4 R exhibited high agonist-independent (constitutive) activity. Most strikingly, the prototypical H 4 R antagonist (1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine) (JNJ7777120) exhibited partial agonistic activity at cH 4 R, rH 4 R, and mH 4 R, whereas at hH 4 R, JNJ7777120 was a partial inverse agonist. H 4 R agonists from the class of N G -acylated imidazolylpropylguanidines and cyanoguanidines exhibited substantial differences in terms of affinity, potency, and efficacy among H 4 R species orthologs, too. The species-dependent pharmacological profiles are not due to the highly variable amino acid sequence position 341. Finally, H 4 R species orthologs differ from each other in terms of regulation by NaCl. Collectively, there are profound pharmacological differences between H 4 R species orthologs. Most importantly, caution must be exerted when interpreting pharmacological effects of “the prototypical H 4 R antagonist” JNJ7777120 as H 4 R antagonism.