Betaarrestin2

Beta-arrestin-2, also known as ARRB2, is a cytosolic adaptor protein that belongs to the arrestin family and is encoded by the ARRB2 gene in humans. It plays a central role in regulating G protein-coupled receptor (GPCR) signaling by promoting desensitization and influencing receptor trafficking.

Upon activation of a GPCR, G protein-centred signaling is attenuated when GPCR kinases (GRKs) phosphorylate the receptor. Beta-arrestin-2 binds to the phosphorylated receptor, preventing further coupling to G proteins. This binding also promotes receptor internalization through clathrin-coated pits, commonly involving interactions with adaptor protein AP-2 and dynamin, and facilitates trafficking of receptors to endosomes. Depending on the receptor and cellular context, the receptor can be recycled back to the plasma membrane or directed toward degradation, contributing to resensitization or downregulation of signaling.

In addition to terminating G protein signaling, beta-arrestin-2 acts as a scaffold for alternative, G protein–independent signaling pathways. It can assemble signaling complexes that activate mitogen-activated protein kinases (MAPKs) such as ERK1/2, JNK, and p38, among others, thereby shaping cellular responses to stimuli.

Beta-arrestin-2 interacts with a wide range of GPCRs, including adrenergic, dopaminergic, muscarinic, and chemokine receptors, reflecting its broad role in modulating receptor activity and endocytosis. It is ubiquitously expressed, with notable presence in the brain, heart, and immune-related tissues.

Physiological and clinical relevance includes involvement in cardiovascular function, pain processing, and CNS signaling, as well as influence on drug tolerance and response. Because of its central role in GPCR regulation, beta-arrestin-2 is studied as a potential target for therapeutic strategies aiming to bias signaling away from G protein pathways or toward arrestin-mediated pathways.