Kenakin Terry
Department of Biochemical Reagents and Assay Development, GlaxoSmithKline Research and Development, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
Trends Pharmacol Sci. 2007 Aug;28(8):407-15. doi: 10.1016/j.tips.2007.06.009. Epub 2007 Jul 13.
Seven-transmembrane receptors are prototypic allosteric proteins with the ability to adopt numerous conformations, many of which interact with cellular partners to initiate cellular biochemical processes. Defining efficacy as the ability of ligands to stabilize some of these conformations (which, in turn, possess physiological activity) presents a wider definition of efficacy beyond simple integrated cellular response; numerous or 'pluridimensional' efficacies are required to describe ligands. Specifically, some agonists might only partially activate the library of potential signaling systems in a cell or some antagonists might actively induce receptor internalization without activation. This article reviews data to demonstrate that there is no longer support for a linear view of efficacy whereby a single receptor activation state triggers all possible receptor interactions with a cell. Instead, a view of collateral efficacy, in which ligands can produce portions of the possible behaviors of receptors, is presented. Concepts related to the molecular mechanism for this effect (discussed in the literature as 'stimulus trafficking', 'biased agonism' or 'functional selectivity') and discussion of the possible therapeutic implications of this mechanism are presented.
七跨膜受体是典型的变构蛋白，能够呈现多种构象，其中许多构象与细胞伴侣相互作用以启动细胞生化过程。将效能定义为配体稳定其中一些构象（这些构象进而具有生理活性）的能力，这给出了一个比简单的综合细胞反应更宽泛的效能定义；描述配体需要多种或“多维度”的效能。具体而言，一些激动剂可能仅部分激活细胞中潜在信号系统的库，或者一些拮抗剂可能在未激活的情况下主动诱导受体内化。本文回顾了相关数据，以证明不再支持效能的线性观点，即单一受体激活状态触发受体与细胞的所有可能相互作用。相反，提出了一种旁系效能观点，即配体可以产生受体可能行为的部分表现。文中介绍了与这种效应的分子机制相关的概念（在文献中讨论为“刺激转运”、“偏向激动作用”或“功能选择性”），并讨论了该机制可能的治疗意义。
