New Insights into Modes of GPCR Activation

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.