Cyclic nucleotide metabolism in rat colonic epithelial cells with different proliferative activities

Abstract

cyclic nucleotide metabolism was examined in rat distal colonic epithelial cells with different proliferative activities. Lower crypt cells had DNA synthetic rates 7–10-fold higher than surface cells. Without a phosphodiesterase inhibitor, proliferative cells had reduced basal cyclic AMP-, cyclic GMP- and cyclic AMP-dependent protein kinase activity ratios, as well as blunted cyclic AMP responses to prostaglandin E 2 and vasoactive intestinal peptide compared to superficial cells. In the presence of 3-isobutyl-1-methylxanthine, basal cyclic AMP and responses to prostaglandin E 2 and vasoactive intestinal peptide of proliferative cells exceeded values in superficial cells. This correlated with higher membrane adenylate cyclase activity in the proliferative cells. By contrast, particullate and soluble guanylate cyclase activities of superficial cells were higher than in proliferative cells. The apparent high K m soluble and particulate cyclic AMP and cyclic GMP phosphodiesterase activities of proliferative cells were 4–7-fold higher than those in superficial cells. Moreover, the apparent low K m soluble activity was absent in superficial cells. Thus, an altered rate of nucleotide degradation may mediate reduced cyclic AMP and cyclic GMP in proliferative versus superficial cells. Dibutyryl cyclic AMP, prostaglandin E 2 or vasoactive intestinal peptide inhibited [ 3H]thymidine incorporation into DNA of colonic segments. Thus, reduced cyclic AMP in lower crypt cells may be a determinant of their greater proliferative activity.