Okadaic acid-induced decrease in the magnitude and ecacy of the Ca 2+ signal in pancreatic b cells and inhibition of insulin secretion - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue British Journal of Pharmacology Année : 1998

Okadaic acid-induced decrease in the magnitude and ecacy of the Ca 2+ signal in pancreatic b cells and inhibition of insulin secretion

Résumé

Phosphorylation by kinases and dephosphorylation by phosphatases markedly aect the biological activity of proteins involved in stimulus-response coupling. In this study, we have characterized the eects 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. 2 Okadaic acid dose-dependently (IC 50 *200 nM) inhibited insulin secretion induced by 15 mM glucose. At 0.5 mM, okadaic acid also inhibited insulin secretion induced by tolbutamide, ketoisocaproate and high K + , and its eects were not reversed by activation of protein kinases A or C. 3 The inhibition of insulin secretion did not result from an alteration of glucose metabolism (estimated by the ¯uorescence of endogenous pyridine nucleotides) or a lowering of the ATP/ADP ratio in the islets. 4 Okadaic acid treatment slightly inhibited voltage-dependent Ca 2+ currents in b 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 insucient to explain the corresponding inhibition of insulin secretion (90%). Moreover, mobilization of intracellular Ca 2+ by acetylcholine was barely aected by okadaic acid, whereas the concomitant insulin response was decreased by 85%. 5 Calyculin A, another inhibitor of protein phosphatases 1 and 2A largely mimicked the eects of okadaic acid, whereas 1-norokadaone, an inactive analogue of okadaic acid on phosphatases, did not alter b cell function. 6 In conclusion, okadaic acid inhibits insulin secretion by decreasing the magnitude of the Ca 2+ signal in b cells and its ecacy on exocytosis. The results suggest that, contrary to current concepts, both phosphorylation and dephosphorylation of certain b cell proteins may be involved in the regulation of insulin secretion.

Dates et versions

hal-04210195 , version 1 (19-09-2023)

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Citer

Yoshihiko Sato, Pascal Mariot, Philippe Detimary, Patrick Gilon, Jean‐claude Henquin. Okadaic acid-induced decrease in the magnitude and ecacy of the Ca 2+ signal in pancreatic b cells and inhibition of insulin secretion. British Journal of Pharmacology, 1998, 123 (1), pp.97-105. ⟨10.1038/sj.bjp.0701578⟩. ⟨hal-04210195⟩
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