DISRUPTION OF THE GUANYLYL CYCLASE-C GENE LEADS TO A PARADOXICAL PHENOTYPE OF VIABLE BUT HEAT-STABLE ENTEROTOXIN-RESISTANT MICE

Heat-stable enterotoxins (STa), which cause an acute secretory diarrhe a, have been suggested to mediate their actions through the guanylyl c yclase-C (GC-C) receptor. The GC-C gene was disrupted by insertion of neo into exon 1 and subsequent homologous recombination. GC-C null mic e contained no detectable GC-C protein. Intestine mucosal guanylyl cyc lase activity was similar to 16-fold higher in wild-type mice than in the GC-C null mice, and STa-stimulable guanylyl cyclase activity was a bsent in the null animals. Thus, GC-C is the major cyclase activity pr esent in the intestine, and also completely accounts for the STa-induc ed elevations of cGMP. Gavage with STa resulted in marked fluid accumu lation within the intestine of wild-type and heterozygous suckling mic e, but GC-C null animals were resistant. In addition, infection with e nterotoxigenic bacteria that produce STa led to diarrhea and death in wild-type and heterozygous mice, while the null mice were protected. C holera toxin, in contrast, continued to cause diarrhea in GC-C null mi ce, demonstrating that the cAMP signaling pathway remained intact. Mar kedly different diets (high carbohydrate, fat, or protein) or the incl usion of high salt (K+, Na+) in the drinking water or diet also did no t severely affect the null animals. Given that GC-C is a major intesti nal receptor in all mammals, the pressure to retain a functional GC-C in the face of diarrhea-inflicted mortality remains unexplained. There fore, GC-C likely provides a protective effect against stressors not y et tested, possibly pathogens other than noninvasive enterotoxigenic b acteria.