DISTINCT RECEPTORS FOR CHOLECYSTOKININ AND GASTRIN ON CANINE FUNDIC D-CELLS

Despite the extensive amino acid homology between gastrin and cholecystokinin (CCK) at the biologically active carboxyl terminus, the receptors through which these peptides exert their action are heterogeneous. In previous studies, we have examined the biological activity of gastrin/CCK peptides on isolated canine fundic D-cells and observed that CCK is a more potent and efficacious stimulant of somatostatin release than gastrin. We performed the present studies to distinguish between distinct CCK (CCK-A subtype) and gastrin (CCK-B/gastrin subtype) receptors on canine D-cells. Consistent with this observation was our finding that the CCK-A receptor selective antagonist L-364,718 dose dependently (10(-11)-10(-7) M) inhibited CCK-mediated somatostatin release but at the same doses did not alter the effect of gastrin. CCK and gastrin exhibited similar potency in displacing bound I-125-labeled Leu15 gastrin-17 from D-cells. However, when I-125-CCK octapeptide (CCK-8) was used as the radioligand, a fraction of the bound label could not be displaced with gastrin, but this fraction was completely displaced with CCK-8. In D-cells pretreated with high concentrations of gastrin, L-364,718 was able to inhibit the gastrin-resistant fraction of I-125-CCK-8 binding, but the CCK-B/gastrin receptor selective antagonist (PD 134308) was unable to influence this fraction of binding in doses as high as 10(-6) M. These studies delineate the presence of distinct CCK-A and CCK-B/gastrin receptors on canine fundic D-cells. Although the maximal stimulatory activity of gastrin on somatostatin release was less than that achieved by CCK, the effect of CCK was not inhibited by gastrin, suggesting that the actions of the two peptides are via separate receptors.