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Articles in PresS, published online ahead of print October 24, 2001
Am J Physiol Gastrointest Liver Physiol, 10.1152/ajpgi.00274.2001
Submitted on June 21, 2001
Accepted on October 9, 2001
1 Physiology, University of Michigan, Ann Arbor, Michigan, USA
2 Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania, USA
* To whom correspondence should be addressed. E-mail: mdsansg{at}umich.edu.
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 translation initiation factor eIF2B. CCK at 10-100 pM did not significantly affect eIF2B activity, which averaged 35.4 nmol GDP exchanged/min/mg protein under control conditions; higher CCK concentrations reduced eIF2B activity to 38.2% of control. Carbachol, A23187 and thapsigargin also inhibited eIF2B and protein synthesis whereas bombesin and the CCK analogue 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 
-subunit of eIF2, which converts it into an inhibitor of eIF2B. CCK, carbachol, A23187, and thapsigargin all enhanced eIF2 phosphorylation suggesting that eIF2B activity is regulated by eIF2 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 eIF2 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 ER lumen leading to phosphorylation of eIF2 and inhibition of eIF2B.
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