Activators of PKA and Epac Distinctly Influence Insulin Secretion and Cytosolic Ca2+in Female Mouse Islets Stimulated by Glucose and Tolbutamide

Jean-Claude Henquin, Myriam Nenquin
2014 Endocrinology  
Amplification of insulin secretion by cAMP is mediated by protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac). Using selective activators, we determined how each effector influences the cytosolic free Ca 2ϩ concentration ([Ca 2ϩ ] c ) and insulin secretion in mouse islets. Alone PKA activator amplified glucose-and tolbutamide-induced insulin secretion, with a greater impact on second than first phase. Epac activator strongly amplified both phases in response to either
more » ... ecretagogue. Amplification was even greater when activators were combined. Although both activators similarly amplified glucose-induced insulin secretion, Epac activator was particularly efficient on tolbutamide-induced insulin secretion. That greater efficacy is attributed to higher [Ca 2ϩ ] c rather than interaction of tolbutamide with Epac, because it was also observed during KCl stimulation. Moreover, in contrast to Epac activator, tolbutamide was inactive when insulin secretion was increased by gliclazide, and its effect on glucose-induced insulin secretion was unaffected by an inhibitor of Epac2. PKA activator increased [Ca 2ϩ ] c during acute or steady-state glucose stimulation, whereas Epac activator had no effect alone or in combination. Neither activator affected [Ca 2ϩ ] c response to tolbutamide or KCl. Metabolic (glucose-mediated) amplification of insulin secretion was unaffected by PKA activator. It was attenuated when insulin secretion was augmented by Epac activator but insensitive to Epac2 inhibitor, which suggests distinct although somewhat overlapping mechanisms. In conclusion, activators of PKA and Epac amplify insulin secretion by augmenting the action of Ca 2ϩ on exocytosis and, for PKA only, slightly increasing glucose-induced [Ca 2ϩ ] c rise. The influence of Epac seems more important than that of PKA during first phase. (Endocrinology 155: 3274 -3287, 2014) Abbreviations: [Ca 2ϩ ] c , cytosolic free Ca 2ϩ concentration; Epac, exchange protein directly activated by cAMP; G3K30, 30mM KCl in 3mM glucose; G15K30, 30mM KCl in 15mM glucose; K ATP , ATP-sensitive potassium; PKA, protein kinase A.
doi:10.1210/en.2014-1247 pmid:24977470 pmcid:PMC4255079 fatcat:d7r7vlyurjev7psas2wepaqqg4