title: Both low- and high-affinity CCK receptor states mediate trophic effects on rat pancreatic acinar cells.
abstract: Cholecystokinin (CCK) stimulates the growth of pancreatic acinar cells. However, the molecular mechanisms involved in this trophic action are unknown. CCK binds to both high- and low-affinity receptor states, and 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 current study, CCK octapeptide (CCK-8) and JMV-180 were tested for their ability to stimulate the growth of rat pancreatic acinar cells in primary culture. CCK-8 stimulated [3H]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 control was stimulated by 100 nM JMV-180. These data with JMV-180 indicate that the high-affinity receptor state for CCK is capable of stimulating DNA synthesis. However, within the same experiment the effects of CCK were always significantly greater than those of JMV-180. To test whether 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 with 1 microM JMV-180. The effects of the combination of 3 nM CCK-8 and 1 microM JMV-180 were no greater than those of JMV-180 alone. Taken together these data indicate that CCK-mediated increases in DNA synthesis in rat pancreatic acinar cells in vitro occur by interactions with both high- and low-affinity receptor states.
authors.affiliation: Department of Physiology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: H
authors.initials: H
authors.lastname: Hoshi
authors.forename: C D
authors.initials: CD
authors.lastname: Logsdon
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D010179:Pancreas / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000187:drug effects / Q000502:physiology*; D012844:Sincalide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014316:Tritium
chemical_list: D011949:Receptors, Cholecystokinin; D014316:Tritium; C058451:JMV 180; D004247:DNA; D012844:Sincalide; D013936:Thymidine