Journal
TRENDS IN PHARMACOLOGICAL SCIENCES
Volume 34, Issue 1, Pages 13-32Publisher
ELSEVIER SCIENCE LONDON
DOI: 10.1016/j.tips.2012.10.004
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Funding
- Deutsche Forschungsgemeinschaft [Se 529/4-1, GRK 760, GRK 1441, SFB 587, STR 1125/1-1]
- European Union (COST program) [BM0806]
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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) - H1R, H2R, H3R, and H4R - 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 HxR 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.
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