Mechanisms by which cyclic nucleotides and other intracellular mediators regulate secretion

The regulation of Na+ and Cl- transport across surface membranes and tight junctions of intestinal epithelium is mediated through at least three intracellular messengers: (i) 3',5'-cyclic AMP, activating two types of cyclic AMP-dependent protein kinase, (ii) 3',5'-cyclic GMP, binding to a unique isoenzyme of cyclic GMP-dependent protein kinase, enriched in the intestinal brush border, and (iii) Ca2+ ions, partially acting through calmodulin and a Ca2+/phospholipid-dependent protein kinase (C kinase). Recent data on the subcellular distribution and molecular properties of the high affinity cyclic nucleotide and Ca2+ receptors, their influence on the phosphorylation state of specific membrane proteins, and the possible role of these target proteins in ion transport regulation, are reviewed. The following aspects are accentuated: (1) the asymmetrical compartmentation of cyclic AMP-dependent protein kinase isoenzymes in the enterocyte and its functional implications; (2) the structure and function of microvillous cyclic GMP-dependent protein kinase; (3) the integration of cyclic AMP and cyclic GMP signals through co-phosphorylation of a 25 000 Mr protein in the intestinal-microvilli; (4) the identification of C kinase in villous and crypt cells; (5) various levels of interaction between cyclic nucleotide and Ca2+ signals; and (6) priority areas for future studies on stimulus-secretion coupling.