Prather Paul L
Department of Pharmacology and Toxicology, Mail Slot 611, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.
Sci STKE. 2004 Jan 5;2004(215):pe1. doi: 10.1126/stke.2152004pe1.
G protein-coupled receptors (GPCRs) traverse the plasma membrane seven times and produce intracellular effects through interaction with G proteins. Three classes of ligands bind and regulate the activity of GPCRs: agonists, antagonists, and inverse agonists. To describe the activity of these ligands at GPCRs, a two-state receptor model has been proposed in which receptors exist in an equilibrium between inactive (R) and active (R*) states. Agonists preferentially bind and stabilize the active (R*) state. This results in an enrichment of the proportion of active receptors, producing an increase in receptor activity. In contrast, inverse agonists preferentially bind and stabilize receptors in the inactive (R) state. This results in an enrichment of the proportion of inactive receptors, producing a reduction in spontaneous receptor activity. Neutral antagonists have equal preferences for both R and R* states, lack any intrinsic activity, and are able to block actions produced by either agonists or inverse agonists. Exciting observations reported in two recent manuscripts by Gbahou et al. and Azzi et al. indicate that some inverse agonists act not only in opposition to agonists by suppressing constitutive receptor activity, but may also initiate unique signal transduction cascades as well. Specifically, it is proposed that these unique ligands are able to enrich several distinct active receptor conformations, each demonstrating a preference for regulation of a discrete intracellular effector. This suggests that inverse agonists are not merely "the opposite of agonists," but instead may serve as useful tools to investigate ligand-specific conformations of GPCRs.
G蛋白偶联受体（GPCRs）七次穿越质膜，并通过与G蛋白相互作用产生细胞内效应。三类配体结合并调节GPCRs的活性：激动剂、拮抗剂和反向激动剂。为了描述这些配体在GPCRs上的活性，人们提出了一种双态受体模型，其中受体在无活性（R）状态和活性（R*）状态之间处于平衡。激动剂优先结合并稳定活性（R*）状态。这导致活性受体比例增加，从而使受体活性增强。相反，反向激动剂优先结合并稳定处于无活性（R）状态的受体。这导致无活性受体比例增加，从而使受体自发活性降低。中性拮抗剂对R和R*状态具有同等偏好，缺乏任何内在活性，并且能够阻断激动剂或反向激动剂产生的作用。Gbahou等人和Azzi等人最近的两篇手稿中报道的令人兴奋的观察结果表明，一些反向激动剂不仅通过抑制组成型受体活性来对抗激动剂，而且还可能启动独特的信号转导级联反应。具体而言，有人提出这些独特的配体能够富集几种不同的活性受体构象，每种构象都表现出对离散细胞内效应器调节的偏好。这表明反向激动剂不仅仅是“激动剂的对立面”，而是可以作为研究GPCRs配体特异性构象的有用工具。
