title: Expression and functional properties of canine, rat, and murine histamine H₄ receptors in Sf9 insect cells.
abstract: The histamine H₄ receptor (H₄R) 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 H₄R in these diseases depends on the use of animal models. However, there are substantial pharmacological differences between various H₄R species orthologs. The purpose of this study was to analyze the pharmacological properties of canine, rat, and murine H₄R in comparison to human H₄R expressed in Sf9 insect cells. Only hH₄R and cH₄R exhibited a sufficiently high [³H]histamine affinity for radioligand binding studies. Generally, cH₄R exhibited lower ligand-affinities than hH₄R. Similarly, in high-affinity GTPase studies, ligands were more potent at hH₄R than at other H₄R species orthologs. Unlike the other H₄R species orthologs, hH₄R exhibited high agonist-independent (constitutive) activity. Most strikingly, the prototypical H₄R antagonist (1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine) (JNJ7777120) exhibited partial agonistic activity at cH₄R, rH₄R, and mH₄R, whereas at hH₄R, JNJ7777120 was a partial inverse agonist. H₄R agonists from the class of N ( G )-acylated imidazolylpropylguanidines and cyanoguanidines exhibited substantial differences in terms of affinity, potency, and efficacy among H₄R species orthologs, too. The species-dependent pharmacological profiles are not due to the highly variable amino acid sequence position 341. Finally, H₄R species orthologs differ from each other in terms of regulation by NaCl. Collectively, there are profound pharmacological differences between H₄R species orthologs. Most importantly, caution must be exerted when interpreting pharmacological effects of "the prototypical H₄R antagonist" JNJ7777120 as H₄R antagonism.
authors.affiliation: Department of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Schnell
authors.forename: Irena
authors.initials: I
authors.lastname: Brunskole
authors.forename: Katerina
authors.initials: K
authors.lastname: Ladova
authors.forename: Erich H
authors.initials: EH
authors.lastname: Schneider
authors.forename: Patrick
authors.initials: P
authors.lastname: Igel
authors.forename: Stefan
authors.initials: S
authors.lastname: Dove
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004285:Dogs; D006632:Histamine / Q000378:metabolism; D006801:Humans; D007313:Insecta; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D011968:Receptors, Histamine / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D000074040:Receptors, Histamine H4; D013045:Species Specificity
chemical_list: C418607:HRH4 protein, human; C498829:Hrh4 protein, mouse; C498828:Hrh4 protein, rat; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D006632:Histamine