Betaarrestins

Beta-arrestins are a family of cytosolic adaptor proteins that regulate signaling by G protein-coupled receptors (GPCRs). The two main mammalian isoforms are beta-arrestin-1 (ARRB1) and beta-arrestin-2 (ARRB2). They are widely expressed and can interact with a broad range of GPCRs.

Beta-arrestins are recruited to activated and phosphorylated GPCRs by receptor kinases (GRKs). Once bound, they sterically prevent further coupling of GPAs to G proteins, thereby desensitizing receptor signaling. In addition, they serve as scaffolds that link receptors to the cellular endocytic machinery, promoting receptor internalization through clathrin-mediated pathways via interactions with clathrin and AP-2. This trafficking can lead to receptor resensitization, recycling back to the membrane, or degradation, depending on the receptor and cellular context.

Beyond desensitization and trafficking, beta-arrestins function as signal transducers independent of G proteins. They scaffold various signaling cascades, including mitogen-activated protein kinases (MAPKs) such as ERK1/2, JNK, and p38, as well as interactions with Src family kinases and PI3K pathways. Through these interactions, beta-arrestins can elicit cellular responses such as changes in gene expression, cytoskeletal remodeling, and altered cell survival.

Physiological and pharmacological significance arises from their dual roles in terminating G protein signaling and initiating arrestin-dependent signaling. This has given rise to the concept of biased agonism, where ligands preferentially activate beta-arrestin pathways over G protein signaling, with potential therapeutic implications and implications for drug side effects. Beta-arrestins remain a focus of research in cardiovascular, neuropsychiatric, and metabolic contexts.