Overview of different mechanisms of arrestin-mediated signaling.

Arrestins are characterized by their ability to selectively bind active, phosphorylated GPCRs and suppress (arrest) receptor coupling to G proteins. Nonvisual arrestins are also signaling proteins in their own right, activating a variety of cellular pathways. Arrestins are highly flexible proteins that can assume many distinct conformations. In their receptor-bound conformation, arrestins have higher affinity for a subset of partners. This explains how receptor activation regulates certain branches of arrestin-dependent signaling via arrestin recruitment to GPCRs. However, free arrestins are also active molecular entities that act in other pathways and localize signaling proteins to particular subcellular compartments, such as cytoskeleton. These functions are regulated by the enhancement or reduction of arrestin affinity for target proteins by other binding partners and by proteolytic cleavage. Recent findings suggest that the two visual arrestins, arrestin-1 and arrestin-4, which are expressed in photoreceptor cells, do not regulate signaling solely via binding to photopigments but also interact with a variety of nonreceptor partners, critically affecting the health and survival of photoreceptor cells. Detailed in this overview are GPCR-dependent and independent modes of arrestin-mediated regulation of cellular signaling pathways.