Requirements of calcium fluxes and ERK kinase activation for glucose- and interleukin-1β-induced β-cell apoptosis

Hongqiang Fei, Bin Zhao, Shangang Zhao, Qin Wang

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Increasing evidence indicates that β-cell apoptosis and impaired secretory function were partly mediated by interleukin (IL)-1β and/ or high-glucose-induced β-cell production of IL-1β. However, the specific signal transduction pathways and molecular events involved in β-cell dysfunction remain largely unresolved. In this study, we investigated whether Ca2+ and extracellular signal-regulated kinase (ERK) activation plays a role for IL-1β action in rat islets. Exposure of rat islets for 4 days to 33.3 mM glucose and 140ng/ml IL-1β-induced β-cell apoptosis and impaired glucose-stimulated insulin secretion. By Western blotting with phosphospecific antibodies, glucose and IL-1β were shown to activate ERK. Ca2+ channel blocker nimodipine or ERK inhibitor PD98059 prevented glucose- and IL-1β-induced ERK activation, β-cell apoptosis, and impaired function. Furthermore, treatment with Ca2+ ionophore ionomycin, or exposure to thapsigargin, an inhibitor of sarco(endo)plasmic reticulum Ca2+ ATPase, all caused an amplification of IL-1β-induced ERK activation in rat islet. On the other hand, a chelator of intracellular free Ca2+ [bis-(o-aminophenoxy)-N,N,N,N-tetraacetic acid-acetoxymethyl] (BAPTA/ AM) and an inhibitor of calmodulin (W7) diminished IL-1β-induced phosphorylation of ERK. Finally, islet release of IL-1β in response to high glucose could be abrogated by nimodipine, mibefradil, or PD98059. Together, these data suggest that glucose- and IL-1β-induced β-cell secretory dysfunction and apoptosis are Ca2+ influx and ERK dependent in rat islets.

Original languageEnglish (US)
Pages (from-to)75-84
Number of pages10
JournalMolecular and Cellular Biochemistry
Volume315
Issue number1-2
DOIs
StatePublished - Aug 2008
Externally publishedYes

Keywords

  • β-cell apoptosis
  • Calcium
  • Diabetes
  • Extracellular signal-regulated kinase (ERK)
  • Interleukin (IL)-1β

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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