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Okadaic acid‐induced decrease in the magnitude and efficacy of the Ca 2+ signal in pancreatic β cells and inhibition of insulin secretion
Author(s) -
Sato Yoshihiko,
Mariot Pascal,
Detimary Philippe,
Gilon Patrick,
Henquin JeanClaude
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701578
Subject(s) - okadaic acid , endocrinology , medicine , pancreatic hormone , secretion , insulin , chemistry , biology , phosphatase , biochemistry , phosphorylation , insulin resistance
Phosphorylation by kinases and dephosphorylation by phosphatases markedly affect the biological activity of proteins involved in stimulus‐response coupling. In this study, we have characterized the effects of okadaic acid, an inhibitor of protein phosphatases 1 and 2A, on insulin secretion. Mouse pancreatic islets were preincubated for 60 min in the presence of okadaic acid before their function was studied. Okadaic acid dose‐dependently (IC 50 ∼200 n M ) inhibited insulin secretion induced by 15 m M glucose. At 0.5 μ M , okadaic acid also inhibited insulin secretion induced by tolbutamide, ketoisocaproate and high K + , and its effects were not reversed by activation of protein kinases A or C. The inhibition of insulin secretion did not result from an alteration of glucose metabolism (estimated by the fluorescence of endogenous pyridine nucleotides) or a lowering of the ATP/ADP ratio in the islets. Okadaic acid treatment slightly inhibited voltage‐dependent Ca 2+ currents in β cells (perforated patch technique), which diminished the rise in cytoplasmic Ca 2+ (fura‐2 method) that glucose and high K + produce in islets. However, this decrease (25%), was insufficient to explain the corresponding inhibition of insulin secretion (90%). Moreover, mobilization of intracellular Ca 2+ by acetylcholine was barely affected by okadaic acid, whereas the concomitant insulin response was decreased by 85%. Calyculin A, another inhibitor of protein phosphatases 1 and 2A largely mimicked the effects of okadaic acid, whereas 1‐norokadaone, an inactive analogue of okadaic acid on phosphatases, did not alter β cell function. In conclusion, okadaic acid inhibits insulin secretion by decreasing the magnitude of the Ca 2+ signal in β cells and its efficacy on exocytosis. The results suggest that, contrary to current concepts, both phosphorylation and dephosphorylation of certain β cell proteins may be involved in the regulation of insulin secretion.British Journal of Pharmacology (1998) 123 , 97–105; doi: 10.1038/sj.bjp.0701578