Dimerization of ?2-adrenergic receptor is responsible for the constitutive activity subjected to inverse agonism

Dimerization of beta 2-adrenergic receptor (02-AR) has been observed across various physiologies. Howev-er, the function of dimeric 02-AR is still elusive. Here, we revealed that dimerization of 02-AR is responsible for the constitutive activity of 02-AR generating inverse agonism. Using a co-immunoimmobilization assay, we found that transient 02-AR dimers exist in a resting state, and the dimer was disrupted by the inverse ago-nists. A Gas preferentially interacts with dimeric 02-AR, but not monomeric 02-AR, in a resting state, resulting in the production of a resting cAMP level. The formation of 02-AR dimers requires cholesterol on the plasma membrane. The cholesterol did not interfere with the agonist-induced activation of monomeric 02-AR, unlike the inverse agonists, implying that the cholesterol is a specific factor regulating the dimerization of 02-AR. Our model not only shows the function of dimeric 02-AR but also provides a molecular insight into the mechanism of the inverse agonism of 02-AR.

Automated summary

This study reveals the importance of dimerization of the β2-adrenergic receptor for generating inverse agonism and identifies cholesterol as a specific regulator in this process.