A novel β_(2)-AR agonist,Higenamine,induces β-arrestin-biased signaling  

作　　者：Nana Zhang Haibo Zhu Zijian Li Erdan Dong 

机构地区：[1]State Key Laboratory for Bioactive Substances and Functions of Natural Medicines/Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study/Institute of Materia Medica,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China [2]Department of Cardiology and Institute of Vascular Medicine,Peking University Third Hospital/Key Laboratory of Cardiovascular Receptors Research,Beijing/Key Laboratory of Molecular Cardiovascular Sciences,Ministry of Education/Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides,Ministry of Health,Beijing 100191,China

出　　处：《Science China(Life Sciences)》2022年第7期1357-1368,共12页中国科学（生命科学英文版）

基　　金：supported by 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(2021-1-I2M028);Disciplines construction project for multi-omics pharmacology(201920200807)。

摘　　要：The biased ligands in G protein-coupled receptors(GPCRs)have opened new avenues for developing safer and more effective drugs.However,the identification of such biased ligands as drug candidates is highly desirable.Here,we report that Higenamine,a compound isolated from a Chinese herb,functions as a novel β-arrestin-biased ligand of the β_(2)-adrenergic receptor(β_(2)-AR).The radioligand binding assays demonstrated that Higenamine was the ligand of β_(2)-AR.Higenamine induced phosphorylation of extracellular signal-regulated kinase 1/2(ERK1/2),which can be blocked by propranolol,an inhibitor of β_(2)-AR.The Gi protein inhibitor,pertussis toxin,had no effect on the phosphorylation of ERK1/2 induced by Higenamine.Furthermore,Higenamine induced ERK1/2 phosphorylation through transactivation of Epithelial growth factor receptor(EGFR).We also found that Higenamine-induced-ERK1/2 phosphorylation is dependent on β-arrestin1/2,and HG inhibits Doxorubicin-induced cardiomyocyte apoptosis.Our results identify Higenamine as a novel biased ligand via the β-arrestin-dependent pathway.These findings give us a better understanding of Higenamine’s potential role in designing diagnostic and therapeutic strategies.

关 键 词：HIGENAMINE β_(2)-adrenergic receptor β-arrestin-biased signaling extracellular signal-regulated kinase 1/2 

分 类 号：R914[医药卫生—药物化学]