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Submitted on July 2, 2004
Accepted on October 15, 2004
INSERM U376, CHU Arnaud-de-Villeneuve, 34295 Montpellier Cedex 5, France; UMR 5160 CNRS, Institut de Biologie-Faculté de Médecine, 34060 Montpellier Cedex 1, France
* To whom correspondence should be addressed. E-mail: dalle{at}montp.inserm.fr.
The p44/p42 Mitogen Activated Protein kinases (ERK1/2) cascade regulates 
cell nuclear events, which modulates cell differentiation and gene transcription, while its implication in processes occurring in the cytoplasm, such as activation of the exocytotic machinery, is still unclear. Using the MIN6 cell line and isolated rat islets of Langerhans, we investigated whether glucose, by activating the ERK1/2 cascade, induces phosphorylation of cytoplasmic proteins implicated in exocytosis of insulin granules such as synapsin I. We observed that the majority of ERK1/2 activity induced by glucose remains in the cytoplasm and physically interacts with synapsin I, allowing phosphorylation of the substrate. Therefore, we re-examined the potential requirement of ERK1/2 for insulin secretion. Blocking activation of ERK1/2 using the MEK1/2 inhibitor PD98059 or using siRNA-mediated silencing of ERK1 and ERK2 expressions resulted in partial inhibition of glucose-induced insulin release, indicating that ERK1/2 pathway participates also to the regulation of insulin secretion. Moreover, using the pancreatic islet perifusion model, we found that the ERK1/2 activity participates in the first and in the second phase of insulin release induced by glucose. Taken together, our results demonstrate new aspects of the glucose-dependent actions of ERK1/2 in cells exerted on cytoplasmic proteins, including synapsin I, and participating in the overall glucose-induced insulin secretion.
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