Cholecystokinin-Induced Inhibition of Endocytosis of Receptor-Bound Substance P in Pancreatic Acinar Cells

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Abstract
Association of 125I-Bolton-Hunter labelled substance P (125I-BH-SP) to suspended pancreatic acinar cells of the guinea pig was studied. Cellular association at 37°C and 22°C was inhibited by cholecystokinin octapeptide (CCK-8) in concentrations from 10−9 to 10−6M, whereas another pancreatic secretagogue, carbachol, was uneffective. The CCK induced inhibition disappeared at low temperatures. CCK-8 mainly interfered with internalization of 125I-BH-SP into acinar cells. Increased extracellular Ca2+ and the Ca2+ ionophores A23187 and ionomycin reduced association of 125I-BH-SP to cells whereas extracellular Ca2+ chelation with EGTA had the opposite effect. However, extra- and intracellular Ca2+ chelation did not affect the degree of CCK-induced reduction of 125I-BH-SP association to acinar cells but eliminated the effect of the calcium ionophore ionomycin. Three agents known to interfere with receptor recycling, namely monensin, methylamine and ammonium chloride reduced cell-associated 125I-BH-SP. In a series of experiments, the cytoplasmic calcium concentrations ([Ca2+) during exposure to these three agents, to the CCK-8-analogue caerulein and to ionomycin were determined. In all cases, [Ca2+] was raised. The results indicate that endocytosis of receptor-bound 125I-BH-SP is regulated by CCK and that the endocytotic process is influenced by calcium.