Critical role of cAMP-GEFII--Rim2 complex in incretin-potentiated insulin secretion.
Incretins such as glucagon-like peptide-1 and gastric inhibitory polypeptide/glucose-dependent insulinotropic peptide are known to potentiate insulin secretion mainly through a cAMP/protein kinase A (PKA) signaling pathway in pancreatic beta-cells, but the mechanism is not clear. We recently found that the cAMP-binding protein cAMP-GEFII (or Epac 2), interacting with Rim2, a target of the small G protein Rab3, mediates cAMP-dependent, PKA-independent exocytosis in a reconstituted system. In the present study, we investigated the role of the cAMP-GEFII--Rim2 pathway in incretin-potentiated insulin secretion in native pancreatic beta-cells. Treatment of pancreatic islets with antisense oligodeoxynucleotides (ODNs) against cAMP-GEFII alone or with the PKA inhibitor H-89 alone inhibited incretin-potentiated insulin secretion approximately 50%, while a combination of antisense ODNs and H-89 inhibited the secretion approximately 80-90%. The effect of cAMP-GEFII on insulin secretion is mediated by Rim2 and depends on intracellular calcium as well as on cAMP. Treatment of the islets with antisense ODNs attenuated both the first and second phases of insulin secretion potentiated by the cAMP analog 8-bromo-cAMP. These results indicate that the PKA-independent mechanism involving the cAMP-GEFII--Rim2 pathway is critical in the potentiation of insulin secretion by incretins.
Kashima
Y
Y
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan.
Miki
T
T
Shibasaki
T
T
Ozaki
N
N
Miyazaki
M
M
Yano
H
H
Seino
S
S
D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D017931:DNA Primers; D019204:GTP-Binding Proteins; D005749:Gastric Inhibitory Polypeptide / Q000502:physiology; D005934:Glucagon / Q000502:physiology; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D007097:Imines / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000502:physiology*; D011498:Protein Precursors / Q000502:physiology
D002352:Carrier Proteins; D017931:DNA Primers; D020662:Guanine Nucleotide Exchange Factors; D007097:Imines; D007328:Insulin; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011498:Protein Precursors; C116122:RAPGEF3 protein, human; C491491:Rims2 protein, mouse; C055453:glucagon-like peptide 1 (7-36)amide; D005749:Gastric Inhibitory Polypeptide; D004763:Glucagon-Like Peptides; C014925:RMI 12330A; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins