New Insights into Modes of GPCR Activation

GPCRs are the largest family of cell surface receptors and are significant drug targets. In recent years, many advanced biochemical and biophysical methods, such as single molecule methods, and single particle electron cryomicroscopy, have been used to study GPCRs. With advanced methods and in-depth research, several novel modes of GPCR activation have been discovered in addition to the classical activation (GPCR–G protein signaling pathways) mode. These diverse modes of GPCR activation help explain their complex behaviors. Varied modes of GPCR activation allow the concept of precision drug development and provide a theoretical basis for the research and development of GPCR-targeted functionally selective drugs. In classical G-protein-coupled receptor (GPCR) activation, GPCRs couple to a variety of heterotrimeric G proteins on the membrane and then activate downstream signaling pathways. More recently, GPCRs have been found to couple to different effector proteins, including different G protein subtypes and regulatory proteins, such as arrestins. Some novel modes of GPCR activation have been proposed to explain their complex behaviors. In this review, we summarize the main novel modes of GPCR activation, including biased activation, intracellular activation, dimerization activation, transactivation, and biphasic activation. In addition, we also discuss the relationship among the five modes to show the complex picture of GPCR activation. The complex activation modes regulate precisely GPCR downstream signaling, including physiological and pathological signaling. Thus, there is the potential to develop GPCR precision drugs that target precise GPCR activation modes to accurately strengthen their beneficial functions and block specific pathological processes. In classical G-protein-coupled receptor (GPCR) activation, GPCRs couple to a variety of heterotrimeric G proteins on the membrane and then activate downstream signaling pathways. More recently, GPCRs have been found to couple to different effector proteins, including different G protein subtypes and regulatory proteins, such as arrestins. Some novel modes of GPCR activation have been proposed to explain their complex behaviors. In this review, we summarize the main novel modes of GPCR activation, including biased activation, intracellular activation, dimerization activation, transactivation, and biphasic activation. In addition, we also discuss the relationship among the five modes to show the complex picture of GPCR activation. The complex activation modes regulate precisely GPCR downstream signaling, including physiological and pathological signaling. Thus, there is the potential to develop GPCR precision drugs that target precise GPCR activation modes to accurately strengthen their beneficial functions and block specific pathological processes.