Species-dependent activities of G-protein-coupled receptor ligands: lessons from histamine receptor orthologs.

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. Copyright © 2012 Elsevier Ltd. All rights reserved.

Citation

Andrea Strasser, Hans-Joachim Wittmann, Armin Buschauer, Erich H Schneider, Roland Seifert. Species-dependent activities of G-protein-coupled receptor ligands: lessons from histamine receptor orthologs. Trends in pharmacological sciences. 2013 Jan;34(1):13-32

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PMID: 23228711

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