title: Activators of PKA and Epac distinctly influence insulin secretion and cytosolic Ca2+ in female mouse islets stimulated by glucose and tolbutamide.
abstract: 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(2+) concentration ([Ca(2+)]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 secretagogue. 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(2+)]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(2+)]c during acute or steady-state glucose stimulation, whereas Epac activator had no effect alone or in combination. Neither activator affected [Ca(2+)]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(2+) on exocytosis and, for PKA only, slightly increasing glucose-induced [Ca(2+)]c rise. The influence of Epac seems more important than that of PKA during first phase.
authors: Unit of Endocrinology and Metabolism, Faculty of Medicine, Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors: Jean-Claude
authors: JC
authors: Henquin
authors: Myriam
authors: M
authors: Nenquin
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D020536:Enzyme Activators / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects; D014044:Tolbutamide / Q000494:pharmacology*
chemical_list: D020536:Enzyme Activators; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; D014044:Tolbutamide; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose; D002118:Calcium