Evidence for cholecystokinin receptor subtype in endocrine pancreas

Abstract

Cholecystokinin (CCK) is a gut hormone that regulates pancreatic endocrine functions via CCK A receptors. CCK 4 (Trp-Met-Asp-Phe-NH 2) has an insulinotropic effect, but is 1000-fold less potent than CCK 8. The in vitro potencies and selectivity of newly synthesized CCK 4 analogs were investigated. Exchanging various a amino acids, for example Met by Nle and modifying Phe and/or Trp, led to compounds that were much more effective than CCK 4 itself and show insulinotropic effects comparable with those of CCK 8. Compounds that possess electron withdrawing groups on the C- terminal phenylalanine were especially effective; compounds with electron-donating groups had no effect. In contrast to CCK 8 the synthetic CCK 4 compounds were selective for the endocrine pancreas: they had no agonistic or antagonistic effect on the contraction of the guinea pig ileum, amylase release from isolated acini, and no major effect on the feeding behavior of mice being supplied with either compound by an implantable Alzet R pump for 8 days. The data indicate that some of the synthetic tetrapeptides exhibit a high affinity for the CCK receptor of the endocrine pancreas and that they are highly selective for this (peripheral) CCK A receptor subtype. The β-cell CCK A receptors are different from those in exocrine pancreas, smooth muscle, and those for regulating appetite; these peripheral receptor subtypes can be discriminated for the first time.