BOTH LOW-AFFINITY AND HIGH-AFFINITY CCK RECEPTOR STATES MEDIATE TROPHIC EFFECTS ON RAT PANCREATIC ACINAR-CELLS

Cholecystokinin (CCK) stimulates the growth of pancreatic acinar cells . However, the molecular mechanisms involved in this trophic action ar e unknown. CCK binds to both high- and low-affinity receptor states, a nd these two states appear to activate separate sets of intracellular messengers and have opposite effects on amylase release. JMV-180 is a CCK analogue that interacts in the rat with the high-affinity state as an agonist and the low-affinity state as an antagonist. In the curren t study, CCK octapeptide (CCK-8) and JMV-180 were tested for their abi lity to stimulate the growth of rat pancreatic acinar cells in primary culture. CCK-8 stimulated [H-3]thymidine incorporation into DNA in a dose-dependent manner. Effects were observed with 0.3 nM, and maximal increases were seen at 3 nM CCK-8 (442 +/- 53% of control, n = 5, P < 0.01). JMV-180 also stimulated DNA synthesis. Effects were noted with 10 nM, and a maximal increase of 267 +/- 82 % (n = 4, P < 0.01) of con trol was stimulated by 100 nM JMV-180. These data with JMV-180 indicat e that the high-affinity receptor state for CCK is capable of stimulat ing DNA synthesis. However, within the same experiment the effects of CCK were always significantly greater than those of JMV-180. To test w hether CCK has an additional effect through interactions with the low- affinity state, the effects of a combination of JMV-180 with a maximal dose of CCK-8 were examined. JMV-180 inhibited the maximal effect of CCK-8 in a dose-dependent manner with a maximal inhibition occurring w ith 1 muM JMV-180. The effects of the combination of 3 nM CCK-8 and 1 muM JMV-180 were no greater than those of JMV-180 alone. Taken togethe r these data indicate that CCK-mediated increases in DNA synthesis in rat pancreatic acinar cells in vitro occur by interactions with both h igh- and low-affinity receptor states.