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Extracellularly Regulated Kinases 1/2 (p44/42 Mitogen-Activated Protein Kinases) Phosphorylate Synapsin I and Regulate Insulin Secretion in the MIN6 ß-Cell Line and Islets of Langerhans

Institut National de la Santé et de la Recherche Médicale Unité 376 (C.L., S.C., E.H.H., D.B., S.D.), Centre Hospitalier Universitaire Arnaud de Villeneuve, 34295 Montpellier Cedex 5, France; and Unité Mixte de Recherche 5160, Centre National de la Recherche Scientifique (C.B.), Institut de Biologie-Faculté de Médecine, 34060 Montpellier Cedex 1, France

Address all correspondence and requests for reprints to: Dr. Stéphane Dalle, Unité Institut National de la Santé et de la Recherche Médecale U376, Centre Hospitalier Universitaire Arnaud de Villeneuve, 371 Rue du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France. E-mail: dalle{at}montp.inserm.fr.

The p44/p42 MAPKs (ERK1/2) cascade regulates ß-cell nuclear events, which modulates cell differentiation and gene transcription, whereas its implication in processes occurring in the cytoplasm, such as activation of the exocytotic machinery, is still unclear. Using the MIN6 ß-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 reexamined the potential requirement of ERK1/2 for insulin secretion. Blocking activation of ERK1/2 using MEK1/2, the MAPK kinase inhibitor PD98059 or using small interfering RNA-mediated silencing of ERK1 and ERK2 expressions resulted in partial inhibition of glucose-induced insulin release, indicating that ERK1/2 pathway participates also in the regulation of insulin secretion. Moreover, using the pancreatic islet perifusion model, we found that the ERK1/2 activity participates in the first and second phases of insulin release induced by glucose. Taken together, our results demonstrate new aspects of the glucose-dependent actions of ERK1/2 in ß-cells exerted on cytoplasmic proteins, including synapsin I, and participating in the overall glucose-induced insulin secretion.

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