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_i) involved in canonical and non-canonical signal transduction, review recent developments and open questions, address the potential of new approaches for targeted pharmacological interventions.

异源三聚体 G 蛋白（G 蛋白）的经典 - 也称为规范 - 细胞信号转导的原始范式是由三个参与者的分层、顺行相互作用定义的：激动剂激活的 G 蛋白偶联受体 (GPCR)，它激活转导 G 蛋白，进而调节其细胞内效应子。这种受体-转导子-效应子的概念通过调节器和适配器的识别得到了扩展，例如 G 蛋白信号传导 (RGS) 的调节器、受体激酶（如 βARK）或 GPCR 相互作用的抑制蛋白适配器，这些适配器在不同水平上整合到该规范信号传导过程中启用微调。最后，经典调节剂非典型信号传导机制的鉴定，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、令人着迷的维度。这组异质的辅助 G 蛋白调节剂被称为“G 蛋白信号传导激活剂”(AGS) 蛋白，在经典和非经典 G 蛋白信号通路中发挥着不同的作用。 AGS 蛋白有助于控制重要的细胞功能，例如细胞发育和分裂、细胞内运输过程、分泌、自噬或细胞运动。因此，它们参与了许多对疾病至关重要的生物过程，例如糖尿病、癌症和中风，这些疾病是主要的健康负担。尽管大量非经典 G 蛋白信号通路的鉴定拓宽了该细胞通讯系统的范围，但它们的潜在机制、功能和生物效应却知之甚少。 在这篇综述中，我们重点讨论了非典型 G 蛋白依赖性信号传导机制，重点关注参与经典和非经典信号转导的抑制性 G 蛋白 (G _i )，回顾了最新进展和悬而未决的问题，解决了新方法的潜力有针对性的药物干预。