ARRB2

ARRB2, also known as beta-arrestin-2, is a member of the arrestin protein family that modulates signaling and trafficking of G protein-coupled receptors (GPCRs). It is encoded by the ARRB2 gene in humans. The primary role of beta-arrestin-2 is to regulate GPCR activity after receptor activation and phosphorylation by GPCR kinases (GRKs). By binding to phosphorylated receptors, ARRB2 blocks further G protein coupling, promoting desensitization, and facilitates receptor internalization via clathrin-coated pits.

Beyond desensitization, beta-arrestin-2 serves as a scaffold for diverse, G protein–independent signaling pathways. It can assemble signaling complexes that activate mitogen-activated protein kinases (MAPKs) such as ERK1/2, JNK, and p38, influencing the duration and spatial dynamics of cellular responses. Through these interactions, ARRB2 shapes signaling outcomes and receptor trafficking, contributing to receptor resensitization and recycling.

ARRB2 is broadly expressed in many tissues, and its subcellular distribution shifts from the cytosol to the plasma membrane and endosomes upon receptor activation. It interacts with a wide range of GPCRs, including adrenergic, dopaminergic, opioid, and angiotensin receptors, among others, reflecting its central role in regulating GPCR networks. The ability of beta-arrestin-2 to channel signaling through arrestin-dependent pathways has contributed to concepts such as biased agonism, where different ligands preferentially activate distinct signaling routes.

In research and clinical contexts, ARRB2 is studied for its roles in cardiovascular, neurological, and immune processes. It is viewed as a potential target to modulate GPCR signaling with improved specificity and reduced desensitization.