BACKGROUND: Cyclic AMP (cAMP) plays a pivotal role in insulin secretion induced by incretins. The effects of the second messenger extend to many sites and there has been much controversy on the mechanisms. The aim of this study was to examine how cAMP amplified insulin exocytosis. METHODS: Rat islets were permeabilized with alpha-toxin to measure insulin exocytosis in the fixed conditions of Ca(2+) and ATP. The effects of several agents on insulin exocytosis were observed in perifusion experiments. RESULTS: Cyclic AMP enhanced the Ca(2+)-induced insulin release by around 30%, independent of Ca(2+) concentrations between 10 and 3000 nmol/L. A cAMP-GEF selective cAMP analogue, 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate, also amplified insulin release. The effect disappeared in the absence of ATP. Conversely, cAMP-independent gradual increase in insulin release was observed with ATP. These results suggested that the site of action of cAMP-GEF existed proximal to that of ATP. An analogue selective to PKA, N(6)-Benzoyladenosine-3',5'-cyclic monophosphate, had little effect. Also, a PKA-selective inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide, reduced insulin releases induced by 1000 nmol/L Ca(2+), but did not influence the relative increase produced by Ca(2+) and cAMP. CONCLUSION: Cyclic AMP potentiated Ca(2+) and ATP-induced exocytosis to a similar relative extent independent of Ca(2+) concentrations. The process appeared to be mainly mediated by cAMP-GEF. In addition, the cAMP/cAMP-GEF pathway may enhance insulin release by replenishing the readily releasable pool. Copyright (c) 2005 John Wiley & Sons, Ltd.
BACKGROUND:Cyclic AMP (cAMP) plays a pivotal role in insulin secretion induced by incretins. The effects of the second messenger extend to many sites and there has been much controversy on the mechanisms. The aim of this study was to examine how cAMP amplified insulin exocytosis. METHODS:Rat islets were permeabilized with alpha-toxin to measure insulin exocytosis in the fixed conditions of Ca(2+) and ATP. The effects of several agents on insulin exocytosis were observed in perifusion experiments. RESULTS:Cyclic AMP enhanced the Ca(2+)-induced insulin release by around 30%, independent of Ca(2+) concentrations between 10 and 3000 nmol/L. A cAMP-GEF selective cAMP analogue, 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate, also amplified insulin release. The effect disappeared in the absence of ATP. Conversely, cAMP-independent gradual increase in insulin release was observed with ATP. These results suggested that the site of action of cAMP-GEF existed proximal to that of ATP. An analogue selective to PKA, N(6)-Benzoyladenosine-3',5'-cyclic monophosphate, had little effect. Also, a PKA-selective inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide, reduced insulin releases induced by 1000 nmol/L Ca(2+), but did not influence the relative increase produced by Ca(2+) and cAMP. CONCLUSION:Cyclic AMP potentiated Ca(2+) and ATP-induced exocytosis to a similar relative extent independent of Ca(2+) concentrations. The process appeared to be mainly mediated by cAMP-GEF. In addition, the cAMP/cAMP-GEF pathway may enhance insulin release by replenishing the readily releasable pool. Copyright (c) 2005 John Wiley & Sons, Ltd.
Authors: Grant G Kelley; Oleg G Chepurny; Frank Schwede; Hans-G Genieser; Colin A Leech; Michael W Roe; Xiangquan Li; Igor Dzhura; Elvira Dzhura; Parisa Afshari; George G Holz Journal: Islets Date: 2009 Nov-Dec Impact factor: 2.694
Authors: Guoxin Kang; Oleg G Chepurny; Brian Malester; Michael J Rindler; Holger Rehmann; Johannes L Bos; Frank Schwede; William A Coetzee; George G Holz Journal: J Physiol Date: 2006-04-13 Impact factor: 5.182
Authors: Oleg G Chepurny; Grant G Kelley; Igor Dzhura; Colin A Leech; Michael W Roe; Elvira Dzhura; Xiangquan Li; Frank Schwede; Hans-G Genieser; George G Holz Journal: Am J Physiol Endocrinol Metab Date: 2009-12-15 Impact factor: 4.310
Authors: Oleg G Chepurny; Colin A Leech; Grant G Kelley; Igor Dzhura; Elvira Dzhura; Xiangquan Li; Michael J Rindler; Frank Schwede; Hans G Genieser; George G Holz Journal: J Biol Chem Date: 2009-02-25 Impact factor: 5.157