Biased signaling of β2-adrenergic receptor in physiological and pathological states

The β2-adrenergic receptor (β2AR), a pivotal member of the G protein-coupled receptor (GPCR) family, plays a crucial role in cellular signaling and is extensively involved in many physiological and pathological processes. Unlike the classical β1AR, the β2AR exhibits unique biased signaling properties. Selective activation of specific downstream pathways, such as the β-arrestin pathway, ERK1/2, and PI3K/Akt, is mediated by ligand binding via biased signaling by a specific G protein, resulting in distinct cellular responses. This review provides an in-depth analysis of the complex mechanisms governing biased β2AR-mediated signaling, highlighting its crucial roles in cardiovascular health, respiratory pathologies, neuroregulatory mechanisms, immunological regulation, and tumor biology. Although β2AR-biased signaling is a well-established phenomenon, its underlying mechanisms and pathophysiological implications remain incompletely elucidated compared with traditional signaling modes. This paper summarizes recent studies on the specificity of β2AR signaling and examines its potential therapeutic applications. Future research should concentrate on clarifying the structural foundations of biased signaling, developing biased ligands, and using these discoveries for precision therapeutics. The therapeutic potential of β2AR-biased signaling is being fully explored, which may open new avenues for personalized treatment of various diseases and bring breakthroughs to the field of clinical medicine.