Beyond desensitization: physiological relevance of arrestin-dependent signaling

Abstract

Heptahelical G protein-coupled receptors are the most diverse and therapeutically important family of receptors in the human genome. Ligand binding activates heterotrimeric G proteins that transmit intracellular signals by regulating effector enzymes or ion channels. G protein signaling is terminated, in large part, by arrestin binding, which uncouples the receptor and G protein and targets the receptor for internalization. It is clear, however, that heptahelical receptor signaling does not end with desensitization. Arrestins bind a host of catalytically active proteins and serve as ligand-regulated scaffolds that recruit protein and lipid kinase, phosphatase, phosphodiesterase, and ubiquitin ligase activity into the receptor-arrestin complex. Although many of these arrestin-bound effectors serve to modulate G protein signaling, degrading second messengers and regulating endocytosis and trafficking, other signals seem to extend beyond the receptor-arrestin complex to regulate such processes as protein translation and gene transcription. Although these findings have led to a re-envisioning of heptahelical receptor signaling, little is known about the physiological roles of arrestin-dependent signaling. In vivo, the duality of arrestin function makes it difficult to dissociate the consequences of arrestin-dependent desensitization from those that might be ascribed to arrestin-mediated signaling. Nonetheless, recent evidence generated using arrestin knockouts, G protein-uncoupled receptor mutants, and arrestin pathway-selective "biased agonists" is beginning to reveal that arrestin signaling plays important roles in the retina, central nervous system, cardiovascular system, bone remodeling, immune system, and cancer. Understanding the signaling roles of arrestins may foster the development of pathway-selective drugs that exploit these pathways for therapeutic benefit.

Fig. 1.

The pleuridimensionality of G protein-coupled receptor signaling. A, classic GPCR signaling arises from heterotrimeric G protein-dependent activation of membrane-delimited effectors [e.g., adenylyl cyclase (AC), phospholipase Cβ isoforms (PLCβ), and ion channels] that generate intracellular second messengers. In the current model, arrestins function as ligand-regulated scaffolds, linking GPCRs to nontraditional effector pathways [e.g., nonreceptor tyrosine kinases (TK), MAP kinases (MAPK), and E3 ubiquitin ligases]. Because arrestin binding precludes further heterotrimeric G protein coupling, these two signaling “states” of the receptor are mutually exclusive. B, G protein-dependent signaling is characterized by rapid onset followed by waning intensity, reflecting progressive desensitization as a result of receptor phosphorylation by second messenger-dependent protein kinases and GRK-dependent arrestin binding. In contrast, arrestin-mediated signals are of somewhat slower onset and often sustained in duration. Unlike G protein signaling, arrestin-dependent signals originate within stoichiometric complexes of receptors, arrestins, and effectors, often termed “signalsomes.”

Fig. 2.

The formation of arrestin-dependent signalsomes affects diverse cellular processes. Given their nearly ubiquitous binding to agonist-occupied GPCRs, it is not surprising that arrestins recruit effector enzymes that promote the degradation of second messengers and regulate GPCR endocytosis and intracellular trafficking, complementing their classic roles in receptor desensitization. Arrestin-based signaling complexes also contribute to membrane and cytosolic processes in which spatially constrained activation of effectors is required, such as vesicle exocytosis, chemotaxis, and phosphorylation-dephosphorylation of cytosolic proteins. Emerging data are also implicating arrestins in transcriptional regulation, where they affect gene expression by attenuating the activity of some pathways and enhancing the activity of others.