G蛋白偶联受体在皮肤与免疫系统中的信号偏向性与下游通路网络互作研究进展
Research Progress on Biased Signaling of G Protein-Coupled Receptors and Their Downstream Pathway Network Interactions in the Skin and Immune System
DOI: 10.12677/pi.2026.152010, PDF,    科研立项经费支持
作者: 马裕添, 岳芸芸*, 尚 靖*：中国药科大学中药学院，江苏 南京
关键词: G蛋白偶联受体；信号转导偏向性；下游通路；交互作用；G Protein-Coupled Receptor； Biased Signaling； Downstream Pathways； Cross-Talk
摘要: G蛋白偶联受体(G Protein-Coupled Receptor, GPCR)是人体内最大的受体家族，参与了广泛的生理过程，并且是许多药物的重要靶点。近年来，研究发现GPCR的配体(ligands)可以通过稳定受体的特定构象，从而选择性地激活下游的某些信号通路，这种现象被称为“信号偏向性”(biased signaling)。这一发现为设计更精准、副作用更小的药物提供了新的思路。本文综述了GPCR激活的经典机制、信号偏向性的分子基础，以及GPCR下游信号通路的核心组成部分，包括cAMP-PKA、PLC-PKC、PI3K-Akt及MAPK级联通路等，聚焦皮肤及免疫系统相关GPCR，并探讨了它们与关键转录因子的调控网络。同时，系统介绍偏向性定量分析方法及不同细胞背景对偏向性评估的影响。文章重点阐述了GPCR偏向性信号产生的机制，包括配体本身带来的偏向、受体自身构象的偏向以及细胞内系统的差异带来的偏向。同时，介绍了近年来结构生物学研究在揭示偏向信号分子机制方面取得的新进展。此外，本文还讨论了GPCR信号通路之间的交叉互作，例如GPCR介导的mTORC2-Akt通路和TGF-β受体通路的整合，以及这些交叉信号在疾病研究和药物开发中的重要意义。最后，对GPCR信号偏向性领域未来的发展方向和面临的挑战进行了展望。
Abstract: G Protein-Coupled Receptors (GPCRs) represent the largest receptor family in the human body, participate in a wide range of physiological processes, and serve as important targets for many therapeutic drugs. In recent years, studies have shown that GPCR ligands can selectively activate specific downstream signaling pathways by stabilizing distinct receptor conformations, a phenomenon known as biased signaling. This discovery has provided new strategies for the development of more precise drugs with reduced adverse effects. This review summarizes the classical mechanisms of GPCR activation, the molecular basis of biased signaling, and the core components of GPCR downstream signaling pathways, including the cAMP-PKA, PLC-PKC, PI3K-Akt, and MAPK cascades. Particular attention is given to GPCRs related to the skin and immune systems, and their regulatory networks with key transcription factors are discussed. In addition, quantitative methods for assessing signaling bias are systematically introduced, along with the influence of different cellular contexts on bias evaluation. The mechanisms underlying GPCR biased signaling are highlighted, including ligand-induced bias, receptor conformational bias, and system-dependent bias arising from intracellular signaling differences. Recent advances in structural biology that have contributed to elucidating the molecular mechanisms of biased signaling are also reviewed. Furthermore, cross-talk among GPCR signaling pathways is discussed, such as the integration of GPCR-mediated mTORC2-Akt signaling with TGF-β receptor pathways, as well as the significance of these interactions in disease research and drug development. Finally, future directions and challenges in the field of GPCR biased signaling are discussed.
文章引用：马裕添, 岳芸芸, 尚靖. G蛋白偶联受体在皮肤与免疫系统中的信号偏向性与下游通路网络互作研究进展[J]. 药物资讯, 2026, 15(2): 74-83. https://doi.org/10.12677/pi.2026.152010

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