Escherichia coli heat-stable enterotoxin (STa)

Escherichia coli heat-stable enterotoxin (ST) is a small, cysteine-rich peptide produced by enterotoxigenic Escherichia coli (ETEC) that acts as a potent secretagogue in the mammalian intestine (UniProt: P01559). It primarily exists in two forms, STa and STb, with STa being the primary cause of traveler's diarrhea in humans by mimicking the endogenous paracrine hormones guanylin and uroguanylin (PubMed: 28416774). Upon entering the intestinal lumen, STa binds with high affinity to the extracellular domain of the transmembrane receptor Guanylate Cyclase C (GC-C) located on the apical surface of enterocytes (PubMed: 25827302). This binding triggers an increase in intracellular cyclic guanosine monophosphate (cGMP), which activates protein kinase G II (PKGII) and inhibits phosphodiesterase 3, leading to the activation of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and the inhibition of the sodium-hydrogen exchanger 3 (NHE3) (StatPearls: ETEC). The resulting net secretion of chloride and bicarbonate ions, along with the inhibition of sodium absorption, creates an osmotic gradient that draws water into the intestinal lumen, causing watery diarrhea (PubMed: 30205260). While the toxin itself is a virulence factor, its pathway has been exploited therapeutically; synthetic analogs like Linaclotide and Plecanatide are used to treat chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) by activating the same GC-C receptor (FDA Label: Linzess).

Other names

Enterotoxin ST-AHeat-stable enterotoxin 1STh (Human)STp (Porcine)ST-AST-1

Binding and activation of the transmembrane receptor Guanylate Cyclase C (GC-C) on intestinal epithelial cells, which stimulates the production of cGMP to induce electrolyte and fluid secretion.