Genetic evidence that b-arrestins are dispensable for the initiation of b₂-adrenergic receptor signaling to ERK

The b₂-adrenergic receptor (b₂AR) has provided a paradigm to elucidate how G protein-coupled receptors (GPCRs) control intracellular signaling, including the discovery that b-arrestins, which bind to ligand-activated GPCRs, are central for GPCR function. We used genome editing, conditional gene deletion, and small interfering RNAs (siRNAs) to determine the roles of b-arrestin 1 (b-arr1) and b-arr2 in b₂AR internalization, trafficking, and signaling to ERK. We found that only b-arr2 was essential for b₂AR internalization. Unexpectedly, b-arr1 and b-arr2 and receptor internalization were dispensable for ERK activation. Instead, b₂AR signaled through Ga_s and Gbg subunits through a pathway that involved the tyrosine kinase SRC, the adaptor protein SHC, the guanine nucleotide exchange factor SOS, the small GTPase RAS, and the kinases RAF and MEK, which led to ERK activation. These findings provide a molecular framework for b₂AR signaling through b-arrestin-independent pathways in key physiological functions and under pathological conditions.