Role of cyclic GMP in the action of heat-stable enterotoxin of Escherichia coli

Abstract

ENTEROTOXIGENIC strains of Escherichia coli elaborate two enterotoxins, a heat-labile toxin (LT) and a heat-stable toxin (ST), which cause diarrhoeal disease in humans1; ST-producing E. coli cause diarrhoea in adult volunteers2 and have been associated with epidemic diarrhoea in a nursery for the newborn3 and with sporadic adult diarrhoea among North American tourists to Latin America4 and the Navajo people in Arizona5. LT-producing strains are identified by the ability of culture filtrates to cause fluid accumulation in rabbit ileal loops at 18 h (ref. 6) or by morphological alteration of Chinese hamster ovary (CHO) cells7 or of Y-l adrenal cells8. ST-producing strains are identified by the ability of culture filtrates to cause earlier fluid accumulation in rabbit ileal loops (peak accumulation at 6 h (ref. 6), or by fluid accumulation in the gut of the suckling mouse at 3 h (refs 9, 10). LT acts in a manner similar to cholera toxin (CT) by activating adenylate cyclase11. The mechanism of action of ST is unknown, however. Culture filtrates of a strain of E. coli that produced both LT and ST caused immediate net fluid secretion in canine jejunal segments without the 1-h delay characteristic of the response to CT12,13. In addition, culture filtrates caused an immediate increase in canine jejunal adenylate cyclase activity as measured by enzymatic generation of P32-cyclic AMP from P32-labelled ATP13, also in contrast to the delay in appearance of increased adenylate cyclase activity following exposure to CT12. The possibility that the early effect of ST was mediated by changes in cyclic nucleotide concentrations was investigated; culture filtrates of ST-producing strains of E. coli caused increased cyclic GMP concentrations in rabbit intestinal tissue and the cyclic GMP analogue 8BrcGMP mimicked ST in magnitude and time course of intestinal fluid accumulation in both rabbits and suckling mice.

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