Dimerization of β2-adrenergic receptor is responsible for the constitutive activity subjected to inverse agonism. Issue 10 (20th October 2022) - Kwon, Yonghoon
Summary: Dimerization of beta 2-adrenergic receptor (β2 -AR) has been observed across various physiologies. However, the function of dimeric β2 -AR is still elusive. Here, we revealed that dimerization of β2 -AR is responsible for the constitutive activity of β2 -AR generating inverse agonism. Using a co-immunoimmobilization assay, we found that transient β2 -AR dimers exist in a resting state, and the dimer was disrupted by the inverse agonists. A Gαs preferentially interacts with dimeric β2 -AR, but not monomeric β2 -AR, in a resting state, resulting in the production of a resting cAMP level. The formation of β2 -AR dimers requires cholesterol on the plasma membrane. The cholesterol did not interfere with the agonist-induced activation of monomeric β2 -AR, unlike the inverse agonists, implying that the cholesterol is a specific factor regulating the dimerization of β2 -AR. Our model not only shows the function of dimeric β2 -AR but also provides a molecular insight into the mechanism of the inverse agonism of β2 -AR. Graphical abstract: Highlights: Single-molecule dimeric β2 -AR is visualized on the plasma membrane of live cells A significant amount of dimeric β2 -AR exists as an active form in the basal state Dimeric β2 -AR regulates constitutive β2 -AR activity Plasma membrane cholesterol is required for the formation of β2 -AR dimerization Abstract : Kwon et al. visualized transient β2-AR dimerization in living cells. A significant amount of β2-AR dimers exist in the basal state, and these were disrupted by inverse agonists. Gαs proteins couple to the dimeric β2-AR in basal state, resulting in cAMP production. The formation of β2-AR dimers requires cholesterol on the plasma membrane.