β-Arrestins not necessary
The β2-adrenergic receptor is thought to activate signaling mediated by the kinase ERK through a pathway that does not require G proteins but rather the β-arrestin family of scaffolding proteins. Biased agonists for the β2-adrenergic receptor are being developed to selectively activate this pathway. O’Hayre et al. took advantage of improved technologies for knocking out proteins in cells and unexpectedly found that β-arrestins were not required for ERK activation downstream of the β2-adrenergic receptor, although β-arrestin 2 was required for receptor internalization. Instead, the pathway depended on Gαs, Gβγ, and various other signaling molecules. These results suggest that biased agonists for the β2-adrenergic receptor may exert their effects in a β-arrestin–independent manner.
