This study tested the hypothesis that diminished exocrine pancreatic function observed in Cu(2+)-deficient rats is associated with alterations in the cholecystokinin (CCK) signal transduction pathway. Male Sprague-Dawley rats were maintained on either a control diet (11 ppm Cu2+) or a Cu(2+)-deficient diet containing 6000 ppm triethylenetetramine tetrahydrochloride. For the duration of the study rats had free access to water and food. After 4 weeks, rats were sacrificed and pancreatic acini isolated for measurement of amylase content, cholecystokinin-stimulated amylase release and total inositol phosphate formation. Plasma Cu2+ levels were significantly (P < 0.05) decreased in rats on a Cu(2+)-deficient diet (19.2 +/- 3.4 micrograms Cu2+/dL), compared with the control diet (77.0 +/- 3.5 micrograms Cu2+/dL). Both amylase content of pancreatic acini and total CCK-8-stimulated amylase release were significantly decreased in Cu(2+)-deficient rats. In addition, Cu(2+)-deficient rats exhibited a decrease (153.5 +/- 30.9%) in the magnitude of CCK-8-stimulated total inositol phosphate formation compared with control rats (220.8 +/- 11.9%). Moreover, CCKA receptor affinity on pancreatic membranes was not significantly altered by Cu(2+)-deficiency, while CCKA receptor density was significantly (P < 0.05) decreased in Cu(2+)-deficient rats. The addition of Cu2+ to the binding assay of Cu(2+)-deficient rats did not restore receptor density to control values. The data demonstrates that adequate dietary intake of Cu2+ is important to maintain the functional integrity of the exocrine pancreas.