Interaction of glucagon-like peptide-I (7-37) and somatostatin-14 on signal transduction and proinsulin gene expression in beta TC-1 cells.
The interactions of glucagon-like peptide-I(7-37)/(7-36)amide (GLP-I) and somatostatin-14 were characterized on the cyclic adenosine monophosphate (cAMP)-dependent signal transduction pathway and on proinsulin gene expression using mouse insulinoma beta TC-1 cells. GLP-I stimulated the activity of adenylate cyclase maximally at 1 mumol/L (151%). This effect was inhibited by 1 mumol/L somatostatin (119%). Forskolin also stimulated adenylate cyclase activity (10 mumol/L forskolin, 265%), and this action was inhibited by somatostatin (220%). Somatostatin alone left the basal adenylate cyclase activity unaltered. Somatostatin reduced the GLP-I-stimulated increase of intracellular cAMP levels (100 nmol/L GLP-I, 141%; 100 nmol/L GLP-I + 1 mumol/L somatostatin, 110%). GLP-I stimulated concentration-dependently the activity of protein kinase A (PKA), with a maximum at 10 nmol/L (181%). This action was inhibited by 100 nmol/L somatostatin (118%), but somatostatin did not influence the basal PKA activity. Furthermore, somatostatin reduced the GLP-I-induced stimulation of proinsulin gene expression (10 nmol/L GLP-I, 176%; 10 nmol/L GLP-I + 1 mumol/L somatostatin, 77%). Somatostatin itself inhibited concentration-dependently proinsulin gene expression (1 mumol/L somatostatin, 53%). These data demonstrate that GLP-I increases the activities of both adenylate cyclase and cAMP-dependent PKA, whereas somatostatin counteracts the stimulatory effect of GLP-I on adenylate cyclase activity, cAMP generation, PKA activity, and proinsulin gene expression. The interaction of both hormones occurs at the level of adenylate cyclase. Therefore, the interaction of both peptide hormones regulates downstream events, including gene expression.
Fehmann
H C
HC
Department of Internal Medicine, Philipps-University of Marburg, Germany.
Strowski
M
M
Göke
B
B
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D004347:Drug Interactions; D015870:Gene Expression / Q000187:drug effects; D000067757:Glucagon-Like Peptide-1 Receptor; D004763:Glucagon-Like Peptides; D007340:Insulinoma / Q000473:pathology*; D051379:Mice; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010455:Peptides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011384:Proinsulin / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000502:physiology; D018027:Receptors, Glucagon; D015398:Signal Transduction / Q000187:drug effects; D013004:Somatostatin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D011956:Receptors, Cell Surface; D018027:Receptors, Glucagon; D005576:Colforsin; D013004:Somatostatin; D004763:Glucagon-Like Peptides; C015236:glucagon-like-immunoreactivity; D011384:Proinsulin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases