Effect of CCK and intracellular calcium to regulate eIF2B and protein synthesis in rat pancreatic acinar cells

Maria Dolors Sans, Scot R. Kimball, John A. Williams

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18 Scopus citations

Abstract

Pancreatic secretagogues enhance acinar protein synthesis at physiological concentrations and inhibit protein synthesis at high concentrations. We investigated the potential role in this process of the eukaryotic translation initiation factor (eIF)2B. Cholecystokinin (CCK) at 10-100 pM did not significantly affect eIF2B activity, which averaged 35.4 nmol guanosine 5′-diphosphate exchanged per minute per milligram protein under control conditions; higher CCK concentrations reduced eIF2B activity to 38.2% of control. Carbamylcholine chloride (Carbachol, CCh), A-23187, and thapsigargin also inhibited eIF2B and protein synthesis, whereas bombesin and the CCK analog JMV-180 were without effect. Previous studies have shown that eIF2B can be negatively regulated by glycogen synthase kinase-3 (GSK-3). However, GSK-3 activity, as assessed by phosphorylation state, was inhibited at high concentrations of CCK, an effect that should have stimulated, rather than repressed, eIF2B activity. An alternative mechanism for regulating eIF2B is through phosphorylation of the α-subunit of eIF2, which converts it into an inhibitor of eIF2B. CCK, CCh, A-23187, and thapsigargin all enhanced eIF2α phosphorylation, suggesting that eIF2B activity is regulated by eIF2α phosphorylation under these conditions. Removal of Ca2+ from the medium enhanced the inhibitory action of CCK on both protein synthesis and eIF2B activity as well as further increasing eIF2α phosphorylation. Although it is likely that other mechanisms account for the stimulation of acinar protein synthesis, these results suggest that the inhibition of acinar protein synthesis by CCK occurs as a result of depletion of Ca2+ from the endoplasmic reticulum lumen leading to phosphorylation of eIF2α and inhibition of eIF2B.

Original languageEnglish (US)
Pages (from-to)G267-G276
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume282
Issue number2 45-2
DOIs
StatePublished - 2002

All Science Journal Classification (ASJC) codes

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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