Calcium-independent potentiation of insulin release by cyclic AMP in single β -cells

• Published in: Nature (London) 1993-05, Vol.363 (6427), p.356-358
• Main Authors: Ämmälä, Carina, Ashcroft, Frances M, Rorsman, Patrik
• Format: Article
• Language: English
• Subjects: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester - pharmacology; 8-Bromo Cyclic Adenosine Monophosphate - pharmacology; Animals; Biochemistry; Biological and medical sciences; Calcium; Calcium - physiology; Cell physiology; Cells, Cultured; Cellular biology; Colforsin - pharmacology; Cyclic AMP - physiology; Enzyme Activation; Exocytosis; Fluorometry; Fundamental and applied biological sciences. Psychology; Hormonal regulation; Hormones; Humanities and Social Sciences; Insulin; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - metabolism; letter; Mice; Molecular and cellular biology; multidisciplinary; Protein Kinase Inhibitors; Protein Kinases - metabolism; Science; Science (multidisciplinary)
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/363356a0

How does cyclic AMP potentiate insulin secretion from pancreatic islet β -cells? This question is fundamental to understanding how hormones such as glucagon, which elevates cAMP 1 , stimulate insulin secretion and so contribute to the normal secretory response of the islet 2,3 . It is well established that a rise in the cytoplasmic Ca 2+ concentration ([Ca 2+ ] i ) is essential for insulin secretion 4 and therefore cAMP has been proposed to act by elevating [Ca 2+ i . But studies on permeabilized β -cells indicate that cAMP increases insulin release even when [Ca 2+ ] i is held constant 5,6 . We have used microfluorimetry and the patch-clamp technique to measure changes simultaneously in Ca 2+ currents, [Ca 2+ ] i and exocytosis 7–9 in a single β -cell in response to cAMP. We show here that cAMP, through activation of protein kinase A, increases Ca2+-influx through voltage-dependent L-type Ca2+ channels, thereby elevating [Ca 2+ ] i and accelerating exocytosis. More importantly, cAMP also promotes insulin release by a direct interaction with the secretory machinery, which accounts for as much as 80% of its effect.