LIGAND-INDUCED REGULATION OF GLUCAGON-LIKE PEPTIDE-I RECEPTOR FUNCTION AND EXPRESSION IN INSULIN-SECRETING BETA-CELLS

Glucagon-like peptide-I (GLP-I) is a potent incretin hormone and media tes 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 funct ion and expression by its own ligand and the cAMP-dependent pathway in rat insulinoma-derived beta cells (RINm5F). The GLP-I receptor underw ent rapid homologous desensitization, which occurred at the receptor l evel. This was characterized by a reduced binding capacity not mediate d by protein kinase A (PKA), GLP-I receptor mRNA levels were downregul ated during incubation of cells by agents increasing cAMP levels inclu ding GLP-I itself, This effect was dependent upon time and concentrati on. Forskolin, the PKA activator ,6-dichloro-1-beta-D-ribofuranosyl-be nzimidazole-3 ,5-monophosphorothiotate, and GLP-I stabilized the GLP-I receptor mRNA, All induced downregulation of the GLP-I receptor numbe r within 3 h, a time point at which GLP-I receptor mRNA levels were no t decreased, This effect was not influenced by cycloheximide. Therefor e, in addition to transcriptional effects, posttranslational mechanism s exist to regulate GLP-I receptor numbers in insulin-secreting cells.