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

Dec 3, 2020The Journal of biological chemistry

Genetic changes and selective drugs that reduce β-arrestin increase cAMP signals at glucagon-related receptors

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Abstract

GLP-1, GIP, and GCGR agonists with reduced β-arrestin-2 recruitment may improve insulin secretion.

  • GLP-1R, GIPR, and GCGR regulate insulin secretion and energy metabolism.
  • Reducing β-arrestin-2 recruitment in GLP-1R agonists has led to promising results in previous studies.
  • In cells lacking both β-arrestin isoforms, cAMP/PKA signaling duration increased in response to the receptors' endogenous ligands.
  • Biased GLP-1, GCG, and GIP analogs showed reduced receptor endocytosis and increased insulin secretion at high concentrations.
  • Biased GCG analogs prolonged cAMP signaling duration without increasing glucose output from liver cells.
  • Further research is required to optimize agonists targeting GLP-1R, GIPR, and GCGR for therapeutic applications.

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