Functional selectivity of G-protein-coupled receptors: From recombinant systems to native human cells

被引:51
|
作者
Seifert, Roland [1 ]
机构
[1] Hannover Med Sch, Inst Pharmacol, D-30625 Hannover, Germany
关键词
G-protein-coupled receptor; Beta-adrenergic receptors; Histamine receptors; Functional selectivity; Receptor models; BETA(2) ADRENERGIC-RECEPTOR; LIGAND-SPECIFIC CONFORMATIONS; ARRESTIN-BIASED AGONISM; HISTAMINE H-2-RECEPTOR; BETA(2)-ADRENERGIC RECEPTOR; INTERNATIONAL UNION; SIGNALING PATHWAYS; MOLECULAR ANALYSIS; HUMAN EOSINOPHILS; ACTIVATION;
D O I
10.1016/j.bcp.2013.07.029
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
In the mid 1990s, it was assumed that a two-state model, postulating an inactive (R) state and an active (R*) state provides the molecular basis for GPCR activation. However, it became clear that this model could not accommodate many experimental observations. Accordingly, the two-state model was superseded by a multi-state model according to which any given ligand stabilizes a unique receptor conformation with distinct capabilities of activating down-stream G-proteins and beta-arrestin. Much of this research was conducted with the beta(2)-adrenoceptor in recombinant systems. At the molecular level, there is now no doubt anymore that ligand-specific receptor conformations, also referred to as functional selectivity, exist. This concept holds great potential for drug discovery in terms of developing drugs with higher selectivity for specific cells and/or cell functions and fewer side effects. A major challenge is the analysis for functional selectivity in native cells. Here, I discuss our current knowledge on functional selectivity of three representative GPCRs, the beta(2)-adrenoceptor and the histamine H-2- and H-4-receptors, in recombinant systems and native human cells. Studies with human neutrophils and eosinophils support the concept of functional selectivity. A major strategy for the analysis of functional selectivity in native cells is to generate complete concentration/response curves with a large set of structurally diverse ligands for multiple parameters. Next, correlations of potencies and efficacies are analyzed, and deviations of the correlations from linearity are indicative for functional selectivity. Additionally, pharmacological inhibitors are used to dissect cell functions from each other. (c) 2013 Elsevier Inc. All rights reserved.
引用
收藏
页码:853 / 861
页数:9
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