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1 Department of Physiology, University of Michigan, Ann Arbor, Michigan 48109; and 2 Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania 17033
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 
-subunit of eIF2,
which converts it into an inhibitor of eIF2B. CCK, CCh, A-23187, 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 endoplasmic reticulum lumen leading to
phosphorylation of eIF2 and inhibition of eIF2B.
protein translation; cholecystokinin; glycogen synthase kinase-3; intracellular calcium
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