Evidence for ligand-specific conformations of the histamine H2-receptor in human eosinophils and neutrophils

The histamine H-2-receptor (H2R) couples to G(s)-proteins and induces adenylyl cyclase-mediated cAMP accumulation. In human neutrophils and eosinophils, the H2R reduces chemotactic peptide-stimulated superoxide anion (O-2(-)) formation. However, pharmacological characterization of the H2R in these cells is far from being complete. The aim of this study was to provide a comprehensive profiling of the H2R in neutrophils and eosinophils. Histamine inhibited O-2(-) formation in human neutrophils more effectively than in eosinophils. H2R agonists mimicked the effects of histamine and H2R antagonists blocked the effects of histamine. We noticed multiple discrepancies in the potencies and efficacies of H2R agonists with respect to cAMP accumulation and inhibition of O-2(-) formation in both cell types. There were also differences in the antagonist profiles between cAMP accumulation and inhibition of O-2(-) formation in neutrophils. Moreover, the pharmacological profile of the recombinant H2R did not match the H2R profile in native cells. The H2R sequence identified in human neutrophils corresponds to the published H2R sequence, excluding the exclusive expression of a new H2R isoform as explanation for the differences. Very likely, the differences between ligands are explained by the existence of ligand-specific receptor conformations with unique affinities, potencies and efficacies. Thus, our data provide evidence for the notion that the concept of ligand-specific receptor conformations can be extended from recombinant systems to native cells. (c) 2012 Elsevier Inc. All rights reserved.