barr2

Barr2 is a common shorthand for beta-arrestin-2, a cytosolic protein encoded by the human ARRB2 gene. It is one of two beta-arrestin family members that regulate G protein-coupled receptor (GPCR) signaling in mammals and across vertebrates.

Function and mechanism

Beta-arrestin-2 serves two main roles in GPCR biology. First, it binds phosphorylated receptors to desensitize G protein signaling, blocking further G protein activation. Second, it acts as a scaffold that assembles signaling complexes, enabling G protein–independent pathways such as MAPK/ERK, JNK, and p38 signaling. Through these actions, beta-arrestin-2 coordinates receptor internalization via clathrin-coated pits and endosomes, linking receptor trafficking to diverse cellular responses.

Structure and regulation

Beta-arrestin-2 consists of two domains with a polar C-terminal tail and an arrestin core that undergoes conformational changes upon receptor engagement. Activation is driven by receptor phosphorylation by GPCR kinases (GRKs), followed by interaction with clathrin and adaptor proteins (such as AP-2). Post-translational modifications, including phosphorylation and ubiquitination, modulate its stability, localization, and signaling bias.

Expression and interactions

ARRB2 is broadly expressed, with notable levels in the brain and peripheral tissues. It interacts with a wide range of GPCRs (for example, adrenergic, dopaminergic, and opioid receptors) and with intracellular kinases such as Raf, MEK, ERK, and Src, enabling cross-talk between receptor desensitization and downstream signaling pathways.

Clinical and research relevance

Because beta-arrestin-2 participates in both desensitization and signaling, it is a focus in studies of biased agonism and receptor pharmacology. Altered ARRB2 function or expression has been explored in contexts such as addiction, mood disorders, and cardiovascular signaling, with ongoing interest in targeting beta-arrestin–mediated pathways for therapeutic benefit.