Research approaches for exploring the hidden conversations of G protein-coupled receptor transactivation

Abstract

G protein-coupled receptor (GPCR) signaling is a crucial physiological mechanism that encompasses a wide range of signaling phenomena. Although traditional GPCR signaling involves G protein or arrestin-related activation, other modes such as biphasic activation, dimer or oligomeric activation, and transactivation have also been observed. Herein, we focus on the increasingly recognized process of GPCR-transactivation. Transactivation refers to the ability of GPCRs to activate other receptor types, especially receptor tyrosine kinases, without engaging their own specific ligands. This cross-talk between GPCRs and other receptors facilitates the integration of multiple signaling pathways, thereby regulating diverse cellular responses, which underscores its physiological significance. In this review, we provide a comprehensive overview of the role of GPCR-transactivation in physiology. We also discuss the growing interest in this field and examine the various tools available for studying transactivation. Additionally, we highlight recent advancements in emerging tools and their application to GPCR-transactivation research. Finally, we propose future research directions and consider the potential impact of new technologies in this rapidly evolving field. Significance Statement: G protein-coupled receptor transactivation plays a key role in integrating multiple signaling pathways by activating other proteins, like receptor tyrosine kinases, without binding their specific ligands. Here, we focus on the significance of transactivation and the various approaches used to study this phenomenon. © 2025 American Society for Pharmacology and Experimental Therapeutics