Pancreas growth, tyrosine kinase, PtdIns 3-kinase, and PLD involve high-affinity CCK-receptor occupation

Abstract

Cholecystokinin (CCK), CCK octapeptide (CCK-8), and caerulein (Cae) are the most potent trophic factors in the pancreas when given exogenously or released from the intestine. Recent studies have suggested that this growth-promoting effect of CCK was initiated through the occupation of the CCKA receptor. This study was then undertaken to determine whether occupation of the high- or low-affinity CCKA receptor is involved in the growth process and to establish which transduction signals have been selectively activated. As an answer to the first question, rats were infused with CCK JMV-180, a CCKA high-affinity agonist, at doses of 50, 100, 150, and 300 micrograms.kg-1.h-1, or Cae (0.25 micrograms.kg-1.h-1) for 4 days. After rats were killed, their pancreatic weight and contents of protein, DNA, RNA, amylase, and chymotrypsinogen were estimated. To investigate the transduction signals, rats were infused for 30 min to 4 h with 300 micrograms.kg-1.h-1 JMV-180, or pancreatic acini were exposed in vitro to 1 microM JMV-180 for 5 or 30 min. After rats were killed, pancreases were used to monitor tyrosine kinase, phosphatidylinositol (PtdIns) 3-kinase, and phospholipase D (PLD) activities. The first set of experiments indicates that JMV-180 caused a dose-dependent effect on pancreas growth, with the 300 micrograms.kg-1 x h-1 dose giving the maximal effect comparable to that of Cae. Furthermore, JMV-180 induced concomitant early increases in tyrosine kinase and PLD activities both in vivo and in vitro and PtdIns 3-kinase in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Phosphatidylinositol 3-kinase-dependent activation of trypsinogen modulates the severity of acute pancreatitis

“…These negative results indicate that the PI3K, which plays a critical role in trypsinogen activation after supramaximal caerulein stimulation, is unlikely to belong to the class I PI3K group. Our results differ from those of another group (27), which has shown formation of class I PI-3K products after stimulation with caerulein. One possible explanation for the differences between our study and theirs is that we have used a supramaximal concentration whereas they have used a maximal concentration of caerulein.…”

Gastrointestinal Hormones Cause Rapid c-Met Receptor Down-regulation by a Novel Mechanism Involving Clathrin-mediated Endocytosis and a Lysosome-dependent Mechanism

“…In pancreatic acini the CCK A receptor subtype has been shown to exist in both a low affinity and a high affinity receptor state, each of which can activate distinct downstream signaling cascades (16,39,(65)(66)(67). A number of our findings support the conclusion that CCK-induced c-Met down-regulation is mediated by the low affinity state but not the high affinity state of the CCK A receptor.…”

“…High affinity CCK A receptor activation causes activation of the phospholipase A 2 and D pathways but not activation of PLC (66,67,76). In contrast, activation of the low affinity CCK A receptor leads to PLC activation, which in turn results in the formation of diacylglycerol and inositol 1,4,5-trisphosphate (66,67,76).…”

Cholecystokinin-stimulated Protein Kinase C-δ Kinase Activation, Tyrosine Phosphorylation, and Translocation Are Mediated by Src Tyrosine Kinases in Pancreatic Acinar Cells

“…10 for the ability of CCK or TPA to stimulate changes in PKC-␦ in pancreatic acini. CCK A receptor activation results in the activation of both phospholipase C and D (38,73,74). Furthermore, CCK A activation activates Src kinases in pancreatic acini (38,44,57).…”