Betaarrestin

Beta-arrestins, or β-arrestins, are cytosolic proteins that regulate G protein-coupled receptor (GPCR) signaling. In mammals, two non-redundant isoforms exist: β-arrestin 1 (ARRB1) and β-arrestin 2 (ARRB2). They regulate GPCR signaling by promoting desensitization and mediating receptor trafficking after phosphorylation by GPCR kinases (GRKs).

Mechanism: Upon receptor activation and phosphorylation, β-arrestins bind to receptors, preventing further G protein coupling, and link the receptor to clathrin and AP-2, promoting endocytosis. They also serve as scaffolds for signaling cascades, notably MAP kinases such as ERK1/2, JNK, and p38, enabling G protein–independent signaling. They can translocate to the nucleus to influence transcription in some contexts.

Distribution and function: β-arrestins are widely expressed, with higher levels in brain, heart, and immune tissues. They regulate receptor trafficking, desensitization, and arrestin-dependent signaling, affecting physiology and disease such as pain, cardiovascular function, metabolism, and cancer progression.

Clinical relevance: Biased agonism describes ligands that preferentially activate β-arrestin–mediated pathways over G protein signaling, offering potential therapeutic benefits with reduced side effects for certain GPCR-targeted drugs. β-arrestins are investigated as drug response determinants and targets, though the relevance of arrestin-mediated signaling varies by receptor and context.

Genetics and models: Mouse models lacking ARRB1 or ARRB2 show distinct phenotypes.