Non-canonical G protein signaling

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.