Disruption of the guanylyl cyclase-C gene leads to a paradoxical phenotype of viable but heat-stable enterotoxin-resistant mice.

Abstract

Heat-stable enterotoxins (STa), which cause an acute secretory diarrhea, have been suggested to mediate their actions through the guanylyl cyclase-C (GC-C) receptor. The GC-C gene was disrupted by insertion of neo into exon 1 and subsequent homologous recombination. GC-C null mice contained no detectable GC-C protein. Intestine mucosal guanylyl cyclase activity was ‫ف‬ 16-fold higher in wild-type mice than in the GC-C null mice, and STa-stimulable guanylyl cyclase activity was absent in the null animals. Thus, GC-C is the major cyclase activity present in the intestine, and also completely accounts for the STa-induced elevations of cGMP. Gavage with STa resulted in marked fluid accumulation within the intestine of wild-type and heterozygous suckling mice, but GC-C null animals were resistant. In addition, infection with enterotoxigenic bacteria that produce STa led to diarrhea and death in wild-type and heterozygous mice, while the null mice were protected. Cholera toxin, in contrast, continued to cause diarrhea in GC-C null mice, demonstrating that the cAMP signaling pathway remained intact. Markedly different diets (high carbohydrate, fat, or protein) or the inclusion of high salt (K ϩ , Na ϩ ) in the drinking water or diet also did not severely affect the null animals. Given that GC-C is a major intestinal receptor in all mammals, the pressure to retain a functional GC-C in the face of diarrhea-inflicted mortality remains unexplained. Therefore, GC-C likely provides a protective effect against stressors not yet tested, possibly pathogens other than noninvasive enterotoxigenic bacteria. ( J. Clin. Invest.

Lack of guanylyl cyclase C, the receptor for Escherichia coli heat‐stable enterotoxin, results in reduced polyp formation and increased apoptosis in the multiple intestinal neoplasia (Min) mouse model

“…It has recently been shown that ST exposure activates calcium influx through cyclic nucleotide-gated channels in rat colonocytes 6 and in T84 cells, where it is associated with decreased proliferation. 2 However, mice lacking GC-C, Gucy2c 2/2 , are viable and fertile with no apparent defects in intestinal morphology or growth 7,8 and there are no differences in crypt depth or villus height (data not shown). Functional studies established that while colonic ion transport is similar to that observed in wild-type mice, 9 bicarbonate secretion in the duodenum of GC-C null mice is greatly attenuated in response to acid, a major physiologic stimulus of secretion.…”

The Regulation and Physiological Roles of the Guanylyl Cyclase Receptors.

“…Gene deletion of murine GC-A, GC-C, ANP, BNP, and CNP along with transgenic over-expression of ANP and BNP have pointed to some of the fundamental roles of these receptors and ligands in murine physiology [168][169][170][171][172][173][174][175][176].…”

“…Disruption of the GC-C gene results in resistance to pathogenic bacteria that secrete STa and cause acute secretary diarrhea [170,171]. GC-C null mice display no prominent abnormal phenotypes in a disease-free, highly controlled environment; intestinal digestive fluid secretion is not disrupted, and high carbohydrate, fat, protein, or salt diets do not adversely affect the null mice [170,171].…”

“…GC-C null mice display no prominent abnormal phenotypes in a disease-free, highly controlled environment; intestinal digestive fluid secretion is not disrupted, and high carbohydrate, fat, protein, or salt diets do not adversely affect the null mice [170,171].…”

Involvement of General Transcriptional Coactivator PC4 in the Transcription of Medaka Fish Intestine-Specific Membrane Guanylyl Cyclase Gene (OlGC6)

“…Thus, GC-C regulates water and ion transport in the intestine (5). On the other hand, GC-C-deficient mice are viable, develop normally, and are fertile, but they are resistant to STa-induced diarrhea (6,7). However, considering that all vertebrates contain an intestine-specific membrane GC gene, this GC may serve some important yet undefined physiological roles.…”