Activation of Intestinal Guanylate Cyclase by Heat-Stable Enterotoxin of Escherichia coli: Studies of Tissue Specificity, Potential Receptors, and Intermediates

Abstract

Heat-stable enterotoxin (ST) of Escherichia coli increased guanylate cyclase activity in homogenates of rat and rabbit intestinal mucosa and stimulated intestinal fluid secretion in suckling mice. The ST effect on guanylate cyclase was dose-dependent, occurred without a time lag, and was confined to the particulate fraction. ST activation of guanylate cyclase was tissue-specific; ST did not alter activity of soluble or particulate rat liver, lung, heart, kidney, or cerebral cortex enzyme. The ST activity on guanylate cyclase and secretion was methanol-soluble and alkali-labile, and its effects were not altered by phentolamine, propranolol, or atropine. Monosialoganglioside did not reduce ST-induced secretion. However, indomethacin and butylated hydroxyanisole decreased the ST effect on both guanylate cyclase and secretion. Fluid secretion with ST sppears to result from specific activation of particulate intestinal guanylate cyclase. While adrenergic and cholinergic events are probably not involved in this process, the effects of ST may be mediated through prostaglandin synthesis or oxidative mechnanisms.

Enteroaggregative Escherichia coli heat-stable enterotoxin 1 represents another subfamily of E. coli heat-stable toxin.

“…STa has been shown to bind directly to and stimulate intestinal guanylate cyclase expressed in COS-7 cells (28). A wealth of additional information has shown that the net result of STa binding to sensitive cells or tissue is cGMP production (29,30), such that it appears certain STa directly stimulates guanylate cyclase in vivo. Guanylin represents a natural ligand for the receptor activating the guanylate cyclase/cGMP cascade.…”

Escherichia colidiarrhoea

“…This occurs only in intestinal epithelial cells and not in a variety of other tissues and cell lines, suggesting that a unique toxin receptor is present in intestinal cells. The mechanism by which increased cGMP leads to a net secretion of water and electrolytes is not well understood, but the action of ST appears to be mainly anti-absorptive and lacks the secretory activity of LT and cholera toxin Guerrant et al 1980). The fluid secretion induced by STB appears to take place with no alteration of cGMP levels, and the mechanism of action of STB remains unknown (Kennedy et al 1984).…”

Guanylyl cyclase C agonists regulate progression through the cell cycle of human colon carcinoma cells

“…ST induces intestinal secretion by binding to guanylyl cyclase C (GC-C), a single transmembrane protein that is expressed exclusively in the brush border of intestinal epithelial cells from the duodenum to the rectum in adult humans (5)(6)(7)(8)(9)(10). Toxin interaction with the extracellular domain activates the cytoplasmic catalytic domain of GC-C, inducing accumulation of intracellular cGMP ([cGMP] i ; ref.…”