The β2-adrenergic receptor (β2-AR) is a typical G-proteincoupled receptor (GPCR) with rich pharmacology and has been targeted for treating various diseases such as asthma, chronic obstructive pulmonary diseases, cardiovascular diseases, and glaucoma. Recently, different GPCR activation modes have been proposed by Li Zijian group to explain their complex behaviors, including biased activation, intracellular activation, dimerization activation, transactivation, and biphasic activation. Accordingly, discovering the ligand’s mode of GPCR activation and identifying the fingerprints of compound profiles is becoming appreciated in modern drug discovery programs, necessitating more informed approaches for compound classification and therapeutic candidate drug selection. Natural products are reservoirs for drug discovery and ERK1/2 activation is an important pathway for assessing the efficacy of β2-AR ligands to discover their precise activation modes.
“Recently, different GPCR activation modes have been proposed to explain their complex behaviors, including biased activation, intracellular activation, dimerization activation, transactivation, and biphasic activation.” said Dr. Nana Zhang, the first author for this work. The results of this research indicated that HG is a ligand of β2-AR, which was demonstrated by radioligand binding assay. HG possessed a unique profile with positive efficacy for β-arrestin-biased ERK1/2 activation, characterized by stimulation EGFR transactivation and Src kinase activity and prevented Doxorubicin-induced apoptosis in cardiomyocytes. “Some experiments revealed that β-arrestin-dependent signaling could be cardioprotective in the presence of chronic catecholamine stimulation, as is the case in heart failure, whereas G protein-dependent signaling may be cardiotoxic under these conditions. The characterization of HG with regard to selective activation of the β-arrestin-ERK1/2 pathway may, in part, explain its pharmacologic effect. It is reasonable to assume that a biased ligand such as HG, which selectively stimulates β-arrestin-mediated signaling, may have therapeutic potential over conventional β2-AR ligands in the abovementioned conditions.” said Professor Li Zijian, the co-corresponding author.
These encouraging results identified that HG is a β2-AR ligand. It possesses a unique signaling profile for stimulating β-arrestin-dependent ERK1/2 activation upon binding to β2-AR, which may be associated with, or be responsible for, its pharmacological effect.
This work was supported by grants from the National Natural Science Foundation of China (91939301, 81820108031, 82070235), Beijing Municipal Natural Science Foundation (7172235, 7191013), Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences（2021RU003), CAMS Innovation Fund for Medical Sciences (No. 2021-1-I2M-028), Disciplines construction project for multi-omics pharmacology (No. 201920200807).
See the article:
Zhang, N., Zhu H., Li, Z., et al. (2021). A novel β2-AR agonist, Higenamine, induces β-arrestin-biased signaling. Sci China Life Sci, in press,
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