Genetic and biased agonist-mediated reductions in β-Arrestin recruitment prolong cAMP signaling at glucagon family receptors

Ben Jones, Emma Rose McGlone, Zijian Fang, Phil Pickford, Ivan R. Corrêa, Atsuro Oishi, Ralf Jockers, Asuka Inoue, Sunil Kumar, Frederik Görlitz, Chris Dunsby, Paul M.W. French, Guy A. Rutter, Tricia Tan, Alejandra Tomas, Stephen R. Bloom

研究成果: Article査読

4 被引用数 (Scopus)

抄録

Receptors for the peptide hormones glucagon-like peptide-1 (GLP-1R), glucose-dependent insulinotropic polypeptide (GIPR), and glucagon (GCGR) are important regulators of insulin secretion and energy metabolism. GLP-1R agonists have been successfully deployed for the treatment of type 2 diabetes, but it has been suggested that their efficacy is limited by target receptor desensitization and downregulation due to recruitment of β-Arrestins. Indeed, recently described GLP-1R agonists with reduced β-Arrestin-2 recruitment have delivered promising results in preclinical and clinical studies. We therefore aimed to determine if the same phenomenon could apply to the closely related GIPR and GCGR. In HEK293 cells depleted of both β-Arrestin isoforms the duration of G protein-dependent cAMP/PKA signaling was increased in response to the endogenous ligand for each receptor. Moreover, in wildtype cells, "biased" GLP-1, GCG, and GIP analogs with selective reductions in β-Arrestin-2 recruitment led to reduced receptor endocytosis and increased insulin secretion over a prolonged stimulation period, although the latter effect was only seen at high agonist concentrations. Biased GCG analogs increased the duration of cAMP signaling, but this did not lead to increased glucose output from hepatocytes. Our study provides a rationale for the development of GLP-1R, GIPR, and GCGR agonists with reduced β-Arrestin recruitment, but further work is needed to maximally exploit this strategy for therapeutic purposes.

本文言語English
論文番号100133
ジャーナルJournal of Biological Chemistry
296
DOI
出版ステータスPublished - 2021 1 1

ASJC Scopus subject areas

  • 生化学
  • 分子生物学
  • 細胞生物学

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