Glucagon-like peptide-1 receptor-mediated endosomal cAMP generation promotes glucose-stimulated insulin secretion in pancreatic β-cells

Am J Physiol Endocrinol Metab. 2013 Jul 15;305(2):E161-70. doi: 10.1152/ajpendo.00551.2012. Epub 2013 Apr 16.

Abstract

Glucagon-like peptide-1 receptor (GLP-1R) plays a major role in promoting glucose-stimulated insulin secretion in pancreatic β-cells. In the present study, we synthesized a novel functional analog of GLP-1 conjugated to tetramethyl rhodamine to monitor the internalization of the receptor. Our data show that after being internalized the receptor is sorted to lysosomes. In endosomes, receptor-ligand complex is found to be colocalized with adenylate cyclase. Pharmacological inhibition of endocytosis attenuates GLP-1R-mediated cAMP generation and consequent downstream protein kinase A substrate phosphorylation and glucose-stimulated insulin secretion. Our study underlines a paradigm shift in GLP-1R signaling and trafficking. The receptor ligand complex triggers cAMP generation both in plasma membrane and in endosomes, which has implications for receptor-mediated regulation of insulin secretion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Blotting, Western
  • Cell Line
  • Cyclic AMP / biosynthesis*
  • Endosomes / metabolism*
  • Exocytosis / physiology
  • Fluorescent Antibody Technique
  • Genes, Reporter
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide-1 Receptor
  • Glucose / pharmacology*
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Luciferases / genetics
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Microscopy, Fluorescence
  • Molecular Sequence Data
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / physiology*
  • Sucrose / pharmacology

Substances

  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Insulin
  • Receptors, Glucagon
  • Sucrose
  • Glucagon-Like Peptide 1
  • Cyclic AMP
  • Luciferases
  • Glucose