title: Species-dependent activities of G-protein-coupled receptor ligands: lessons from histamine receptor orthologs.
abstract: Histamine is a biogenic amine that exerts its biological effects as a neurotransmitter and local mediator via four histamine receptor (HR) subtypes (H(x)Rs) - H(1)R, H(2)R, H(3)R, and H(4)R - belonging to the superfamily of G-protein-coupled receptors (GPCRs). All four H(x)Rs exhibit pronounced differences in agonist and/or antagonist pharmacology among various species orthologs. The species differences constitute a problem for animal experiments and drug development. This problem applies to GPCRs with diverse ligands. Here, we summarize our current knowledge on H(x)R orthologs as a case study for species-dependent activity of GPCR ligands. We show that species-specific pharmacology also provides unique opportunities to study important aspects of GPCR pharmacology in general, including ligand-binding sites, the roles of extracellular domains in ligand binding and receptor activation, agonist-independent (constitutive) receptor activity, thermodynamics of ligand/receptor interaction, receptor-activation mechanisms, and ligand-specific receptor conformations.
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry II, University of Regensburg, Regensburg, Germany. andrea.strasser@chemie.uni-regensburg.de
authors.forename: Andrea
authors.initials: A
authors.lastname: Strasser
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Wittmann
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
authors.forename: Erich H
authors.initials: EH
authors.lastname: Schneider
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
mesh_terms: D000818:Animals; D006632:Histamine / Q000737:chemistry / Q000494:pharmacology; D017442:Histamine Agonists / Q000737:chemistry / Q000494:pharmacology; D006633:Histamine Antagonists / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D011968:Receptors, Histamine / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D013045:Species Specificity
chemical_list: D017442:Histamine Agonists; D006633:Histamine Antagonists; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D006632:Histamine