arrestin

Arrestins are a family of cytosolic proteins that regulate signaling and trafficking of G protein-coupled receptors (GPCRs). In vertebrates, four arrestins are known: two visual arrestins expressed in photoreceptors and two non-visual beta-arrestins involved in GPCR regulation across tissues.

When a GPCR is activated by a ligand, GPCR kinases (GRKs) phosphorylate the receptor; arrestin binds preferentially to the phosphorylated receptor in its active conformation. This binding blocks further G protein coupling, causing desensitization of G protein signaling. Arrestin also links the receptor to components of the endocytic machinery, such as clathrin and AP-2, promoting clathrin-mediated internalization. After internalization, receptors may be sorted to recycling endosomes or lysosomes for degradation.

Beyond desensitization, arrestins act as scaffolds that assemble signaling complexes, enabling G protein–independent pathways such as MAPK/ERK, JNK, and AKT. This activity has given rise to the concept of biased agonism, where ligands preferentially activate arrestin-mediated signaling over G protein–mediated pathways.

Arrestins have essential roles in vision, regulating rod and cone opsins; in other tissues, they regulate diverse physiological processes and can influence receptor sensitivity, trafficking, and signaling duration. Research on arrestin structure, interactions, and function continues to illuminate GPCR biology and has implications for drug discovery targeting GPCR pathways.