From Escherichia coli heat-stable enterotoxin to mammalian endogenous guanylin hormones

Abstract

The isolation of heat-stable enterotoxin (STa) from Escherichia coli and cholera toxin from Vibrio cholerae has increased our knowledge of specific mechanisms of action that could be used as pharmacological tools to understand the guanylyl cyclase-C and the adenylyl cyclase enzymatic systems. These discoveries have also been instrumental in increasing our understanding of the basic mechanisms that control the electrolyte and water balance in the gut, kidney, and urinary tracts under normal conditions and in disease. Herein, we review the evolution of genes of the guanylin family and STa genes from bacteria to fish and mammals. We also describe new developments and perspectives regarding these novel bacterial compounds and peptide hormones that act in electrolyte and water balance. The available data point toward new therapeutic perspectives for pathological features such as functional gastrointestinal disorders associated with constipation, colorectal cancer, cystic fibrosis, asthma, hypertension, gastrointestinal barrier function damage associated with enteropathy, enteric infection, malnutrition, satiety, food preferences, obesity, metabolic syndrome, and effects on behavior and brain disorders such as attention deficit, hyperactivity disorder, and schizophrenia.

Animal Enterotoxigenic Escherichia coli

“…STa toxins are synthesized as larger precursors (72 a.a.) that are later cleaved into the active mature toxin (367, 368). Six cysteine residues involved in disulfide bond formation are present at the same position in STaH and STaP (Table 8).…”

Guanylyl cyclase C signaling axis and colon cancer prevention

“…Exogenous STa is a molecular mimic of two endogenous peptide ligands, which also function as GUCY2C agonists. These ligands, guanylin (GUCA2A) and uroguanylin (GUCA2B), both expressed in gut epithelial cells[ 15 , 35 , 36 ], act locally as autocrine and paracrine hormones to regulate GUCY2C signaling and fluid and electrolyte homeostasis[ 28 , 31 ]. Additionally, uroguanylin acts as an endocrine hormone, secreted into the systemic circulation postprandially to activate hypothalamic GUCY2C and induce satiety[ 37 - 39 ].…”

“…First, guanylin and uroguanylin have 10- to 100-fold lower affinities for GUCY2C than STa. Further, unlike STa, which contains three disulfide bonds, guanylin and uroguanylin contain only two disulfide bonds, increasing their susceptibility to proteolytic degradation in the gut lumen in comparison to STs[ 16 , 35 ].…”

Molecular Mechanism of Cholerae Toxin (ctx) in Causing Diarrhea

“…The Gs protein plays a role in converting the inactive adenilate cyclase (AC) into active AC then the increase of AC activity will increase the cyclic adenosine 3'5'-monophosphate (cAMP) concentration along the cell membrane. Furthermore, cAMP causes active secretion of sodium (Na + ), chloride (Cl -), potassium (K + ), bicarbonate (HCO3 -), and water (H2O) exit from cells to the intestinal lumen resulting in large fluid losses and electrolyte imbalances (Ryan and Ray, 2004;Thiagarajah and Verkman, 2005;Lima and Fonteles, 2015). The clinical features of cholera are diarrhea and the occurrence of dehydration as a result of fluid loss through feces.…”