期刊
CELL CHEMICAL BIOLOGY
卷 29, 期 10, 页码 1532-+出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2022.09.001
关键词
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资金
- National Research Foundation of Korea (NRF) grant [NRF-2019R1A2C2002152]
- Global Research Laboratory (GRL) Program - Ministry of Science and ICT of Korea [NRF-2016K1A1A2912722]
- California Tobacco-Related Disease Research Program of University of California [T32FT4691]
- National Research Foundation of Korea [NRF-2020R1C1C1008823, NRF-2017R1A5A1015366]
- Brain Korea 21 FOUR
- National Research Foundation of Korea [2016K1A1A2912722] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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.
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.
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