title: Glucagon-like peptide-1 receptor-mediated endosomal cAMP generation promotes glucose-stimulated insulin secretion in pancreatic β-cells.
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.
authors.affiliation: Chemical Biology Program, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, India.
authors.forename: Ramya S
authors.initials: RS
authors.lastname: Kuna
authors.forename: Shravan Babu
authors.initials: SB
authors.lastname: Girada
authors.forename: Suman
authors.initials: S
authors.lastname: Asalla
authors.forename: Joyprashant
authors.initials: J
authors.lastname: Vallentyne
authors.forename: Subbareddy
authors.initials: S
authors.lastname: Maddika
authors.forename: James T
authors.initials: JT
authors.lastname: Patterson
authors.forename: David L
authors.initials: DL
authors.lastname: Smiley
authors.forename: Richard D
authors.initials: RD
authors.lastname: DiMarchi
authors.forename: Prasenjit
authors.initials: P
authors.lastname: Mitra
mesh_terms: D000595:Amino Acid Sequence; D015153:Blotting, Western; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis*; D011992:Endosomes / Q000378:metabolism*; D005089:Exocytosis / Q000502:physiology; D005455:Fluorescent Antibody Technique; D017930:Genes, Reporter; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D018027:Receptors, Glucagon / Q000235:genetics / Q000502:physiology*; D013395:Sucrose / Q000494:pharmacology
chemical_list: C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D018027:Receptors, Glucagon; D013395:Sucrose; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D008156:Luciferases; D005947:Glucose