Department of Pharmacology, Experimental Therapy and Toxicology, Institute of Experimental and Clinical Pharmacology and Pharmacogenomics, and ICePhA Mouse Clinic, University of Tübingen, Wilhelmstraße 56, D-72074 Tübingen, Germany.
Department of Pharmacology, Experimental Therapy and Toxicology, Institute of Experimental and Clinical Pharmacology and Pharmacogenomics, and ICePhA Mouse Clinic, University of Tübingen, Wilhelmstraße 56, D-72074 Tübingen, Germany.
Pharmacol Ther. 2024 Mar;255:108589. doi: 10.1016/j.pharmthera.2024.108589. Epub 2024 Jan 29.
The original paradigm of classical - also referred to as canonical - cellular signal transduction of heterotrimeric G proteins (G protein) is defined by a hierarchical, orthograde interaction of three players: the agonist-activated G protein-coupled receptor (GPCR), which activates the transducing G protein, that in turn regulates its intracellular effectors. This receptor-transducer-effector concept was extended by the identification of regulators and adapters such as the regulators of G protein signaling (RGS), receptor kinases like βARK, or GPCR-interacting arrestin adapters that are integrated into this canonical signaling process at different levels to enable fine-tuning. Finally, the identification of atypical signaling mechanisms of classical regulators, together with the discovery of novel modulators, added a new and fascinating dimension to the cellular G protein signal transduction. This heterogeneous group of accessory G protein modulators was coined "activators of G protein signaling" (AGS) proteins and plays distinct roles in canonical and non-canonical G protein signaling pathways. AGS proteins contribute to the control of essential cellular functions such as cell development and division, intracellular transport processes, secretion, autophagy or cell movements. As such, they are involved in numerous biological processes that are crucial for diseases, like diabetes mellitus, cancer, and stroke, which represent major health burdens. Although the identification of a large number of non-canonical G protein signaling pathways has broadened the spectrum of this cellular communication system, their underlying mechanisms, functions, and biological effects are poorly understood. In this review, we highlight and discuss atypical G protein-dependent signaling mechanisms with a focus on inhibitory G proteins (G) involved in canonical and non-canonical signal transduction, review recent developments and open questions, address the potential of new approaches for targeted pharmacological interventions.
经典（也称为规范）细胞信号转导的异三聚体 G 蛋白（G 蛋白）的原始范例由三个参与者的层次结构、正交相互作用定义：激动剂激活的 G 蛋白偶联受体（GPCR），它激活转导 G 蛋白，G 蛋白反过来调节其细胞内效应物。这种受体-转导子-效应器的概念通过鉴定调节剂和接头（如 G 蛋白信号转导调节剂（RGS）、βARK 样受体激酶或 GPCR 相互作用的阻滞蛋白接头）得到扩展，这些调节剂和接头在不同水平整合到这个规范信号转导过程中，以实现精细调节。最后，经典调节剂的非典型信号机制的鉴定，以及新型调节剂的发现，为细胞 G 蛋白信号转导增添了一个新的迷人维度。这种经典调节物的非典型信号机制的鉴定，以及新型调节剂的发现，为细胞 G 蛋白信号转导增添了一个新的迷人维度。这种异质的辅助 G 蛋白调节剂群体被称为“G 蛋白信号转导激活剂”（AGS）蛋白，它们在规范和非规范 G 蛋白信号通路中发挥不同的作用。AGS 蛋白在细胞发育和分裂、细胞内运输过程、分泌、自噬或细胞运动等基本细胞功能的控制中发挥作用。因此，它们参与了许多对疾病至关重要的生物学过程，如糖尿病、癌症和中风，这些疾病都是重大的健康负担。尽管大量非规范 G 蛋白信号通路的鉴定拓宽了这个细胞通讯系统的范围，但它们的潜在机制、功能和生物学效应仍知之甚少。在这篇综述中，我们重点介绍和讨论了非典型 G 蛋白依赖性信号机制，特别是涉及规范和非规范信号转导的抑制性 G 蛋白（G），回顾了最近的发展和未解决的问题，探讨了新的靶向药理学干预方法的潜力。
