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Glycyrrhetic acid (GA) exerts synergistic anti-asthmatic effects via a β 2 -adrenergic receptor (β 2 AR)-mediated pathway. Cholesterol is an important component of the structure and function of lipid rafts, which play critical roles in the β 2 AR-Gs-adenylate cyclase (AC)-mediated signaling pathway. Owing to the structural similarities between GA and cholesterol, we investigated the possibility that GA enhances β 2 AR signaling by altering cholesterol distribution. Azide-terminal GA (ATGA) was synthesized and applied to human embryonic kidney 293 (HEK293) cells expressing fusion β 2 AR, and the electron spin resonance (ESR) technique was utilized. GA was determined to be localized predominantly on membrane and decreased their cholesterol contents. Thus, the fluidity of the hydrophobic region increased but not the polar surface of the cell membrane. The conformations of membrane proteins were also changed. GA further changed the localization of Gαs from lipid rafts to non-raft regions, resulting the binding of β 2 AR and Gαs, as well as in reduced β 2 AR internalization. Co-localization of β 2 AR, Gαs, and AC increased isoproterenol-induced cAMP production and cholesterol reloading attenuated this effect. A speculation wherein GA enhances beta-adrenergic activity by increasing the functional linkage between the subcomponents of the membrane β 2 AR-protein kinase A (PKA) signaling pathway was proposed. The enhanced efficacy of β 2 AR agonists by this novel mechanism could prevent tachyphylaxis.

Glycyrrhetic Acid Synergistically Enhances β2-Adrenergic Receptor-Gs Signaling by Changing the Location of Gαs in Lipid Rafts