Arrestins as rheostats of GPCR signalling

G protein-coupled receptors (GPCRs) have a central role in a myriad of physiological functions and their dysregulation underlies some of the most prevalent human diseases. They control cell behaviour and cell fate by recruiting and activating intracellular molecules such as heterotrimeric G proteins and arrestins, both of which take active roles in GPCR signalling. G proteins have been viewed as the main signal transducers, whereas arrestins were originally associated with signalling desensitization. Nevertheless, some studies have demonstrated G protein-independent roles of arrestins in GPCR signal transduction. In this Comment, we highlight recent key findings obtained with genome-edited cells to suggest that arrestins — rather than being active transducers in their own right — are key modulators of G protein-initiated signal transmission, thereby shaping and fine-tuning dynamic GPCR responses in space and time. G protein coupled receptors (GPCRs) transmit a variety of signals, mostly by engaging G proteins, but G protein-independent signalling through arrestins has also been demonstrated. Based on recent experimental evidence, Gutkind and Kostenis argue that arrestins serve as important signal modulators instead of as independent signal transducers.