title: Ligand-induced regulation of glucagon-like peptide-I receptor function and expression in insulin-secreting beta cells.
abstract: Glucagon-like peptide-I (GLP-I) is a potent incretin hormone and mediates its actions via the cyclic AMP (cAMP) pathway. The GLP-I receptor belongs to the family of seven-transmembrane domain receptors coupled to G proteins. We have analyzed the regulation of GLP-I receptor function and expression by its own ligand and the cAMP-dependent pathway in rat insulinoma-derived beta cells (RINm5F). The GLP-I receptor underwent rapid homologous desensitization, which occurred at the receptor level. This was characterized by a reduced binding capacity not mediated by protein kinase A (PKA). GLP-I receptor mRNA levels were down-regulated during incubation of cells by agents increasing cAMP levels including GLP-I itself. This effect was dependent upon time and concentration. Forskolin, the PKA activator 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole-3, 5-monophosphorothiotate, and GLP-I stabilized the GLP-I receptor mRNA. All induced down-regulation of the GLP-I receptor number within 3 h, a time point at which GLP-I receptor mRNA levels were not decreased. This effect was not influenced by cycloheximide. Therefore, in addition to transcriptional effects, posttranslational mechanisms exist to regulate GLP-I receptor numbers in insulin-secreting cells.
authors.affiliation: Department of Medicine, Philipps-University of Marburg, Germany.
authors.forename: H C
authors.initials: HC
authors.lastname: Fehmann
authors.forename: J
authors.initials: J
authors.lastname: Jiang
authors.forename: D
authors.initials: D
authors.lastname: Pitt
authors.forename: J
authors.initials: J
authors.lastname: Schweinfurth
authors.forename: B
authors.initials: B
authors.lastname: Göke
mesh_terms: D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D005934:Glucagon / Q000378:metabolism / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007340:Insulinoma; D007515:Islets of Langerhans / Q000378:metabolism*; D010190:Pancreatic Neoplasms; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D011498:Protein Precursors / Q000378:metabolism / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018027:Receptors, Glucagon / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D018027:Receptors, Glucagon; D005576:Colforsin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D003513:Cycloheximide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases