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

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)