Inverse Agonists: Tools to Reveal Ligand-Specific Conformations of G Protein–Coupled Receptors
Inverse Agonists: Tools to Reveal Ligand-Specific Conformations of G Protein–Coupled Receptors
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反向激动剂：揭示 G 蛋白偶联受体配体特异性构象的工具
DOI：
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发表时间：
2004
期刊：
影响因子：
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通讯作者：
P. Prather
中科院分区：
文献类型：
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作者：
P. Prather
G 蛋白偶联受体 (GPCR) 穿过质膜七次，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 GPCR 的活性：激动剂、拮抗剂和反向激动剂。为了描述这些配体在 GPCR 上的活性，提出了一种双态受体模型，其中受体处于非活性 (R) 和活性 (R*) 状态之间的平衡状态。激动剂优先结合并稳定活性 (R*) 状态。这导致活性受体比例的增加，从而导致受体活性的增加。相反，反向激动剂优先结合并稳定非活性 (R) 状态的受体。这导致非活性受体比例增加，导致自发受体活性降低。中性拮抗剂对 R 和 R* 状态具有相同的偏好，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 等人最近的两份手稿报告了令人兴奋的观察结果。和阿齐等人。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。具体来说，建议这些独特的配体能够丰富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的调节的偏好。这表明反向激动剂不仅仅是“激动剂的相反”，而且可以作为研究 GPCR 配体特异性构象的有用工具。
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.