Species-dependent activities of G-protein-coupled receptor ligands: lessons from histamine receptor orthologs.
Species-dependent activities of G-protein-coupled receptor ligands: lessons from histamine receptor orthologs.
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DOI：
10.1016/j.tips.2012.10.004
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发表时间：
2013
影响因子：
13.8
通讯作者：
A. Strasser;Hans-Joachim Wittmann;A. Buschauer;E. Schneider;R. Seifert
中科院分区：
文献类型：
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作者：
A. Strasser;Hans-Joachim Wittmann;A. Buschauer;E. Schneider;R. Seifert
组胺是一种生物胺，通过属于 G 蛋白偶联受体 (GPCR) 超家族的四种组胺受体 (HR) 亚型 (HxR)（H1R、H2R、H3R 和 H4R）发挥其作为神经递质和局部介质的生物作用。所有四种 HxR 在不同物种的直系同源物中都表现出激动剂和/或拮抗剂药理学的显着差异。物种差异构成了动物实验和药物开发的问题。这个问题适用于具有不同配体的 GPCR。在这里，我们总结了目前对 HxR 直系同源物的了解，作为 GPCR 配体物种依赖性活性的案例研究。我们表明，物种特异性药理学还为研究 GPCR 药理学的重要方面提供了独特的机会，包括配体结合位点、胞外结构域在配体结合和受体激活中的作用、激动剂独立（组成型）受体活性、配体/受体相互作用的热力学、受体激活机制和配体特异性受体构象。
Histamine is a biogenic amine that exerts its biological effects as a neurotransmitter and local mediator via four histamine receptor (HR) subtypes (HxRs) – H1R, H2R, H3R, and H4R – belonging to the superfamily of G-protein-coupled receptors (GPCRs). All four HxRs 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.