Evidence for ligand-specific conformations of the histamine H(2)-receptor in human eosinophils and neutrophils.

The histamine H(2)-receptor (H(2)R) couples to G(S)-proteins and induces adenylyl cyclase-mediated cAMP accumulation. In human neutrophils and eosinophils, the H(2)R reduces chemotactic peptide-stimulated superoxide anion (O(2)(-)) formation. However, pharmacological characterization of the H(2)R in these cells is far from being complete. The aim of this study was to provide a comprehensive profiling of the H(2)R in neutrophils and eosinophils. Histamine inhibited O(2)(-) formation in human neutrophils more effectively than in eosinophils. H(2)R agonists mimicked the effects of histamine and H(2)R antagonists blocked the effects of histamine. We noticed multiple discrepancies in the potencies and efficacies of H(2)R 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 H(2)R did not match the H(2)R profile in native cells. The H(2)R sequence identified in human neutrophils corresponds to the published H(2)R sequence, excluding the exclusive expression of a new H(2)R 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.