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.He...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.展开更多
基金supported by the National Natural Science Foundation of China(91939301,81820108031,82070235)Beijing Municipal Natural Science Foundation(7172235,7191013)+2 种基金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)。
文摘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.
