Guanylate cyclase C (GC-C) (GC-C)

Guanylate cyclase C (GC-C) is a transmembrane receptor and enzyme primarily expressed on the apical membrane of intestinal epithelial cells (UniProt P25092). It serves as the physiological receptor for the endogenous peptides guanylin and uroguanylin, and it is the primary target for the bacterial heat-stable enterotoxin (STa) produced by enterotoxigenic Escherichia coli (ETEC) (PubMed: 2010 review, PMC: Cure and Curse). Activation of GC-C by these ligands triggers the synthesis of cyclic GMP (cGMP), which acts as a second messenger to regulate ion transport and fluid homeostasis in the gut (ResearchGate: Mechanism of action). In ETEC infections, the overactivation of GC-C by STa leads to profuse secretory diarrhea (PMC: Heat-stable enterotoxins and immunity). Conversely, synthetic agonists of GC-C, such as linaclotide and plecanatide, are therapeutically utilized to treat chronic idiopathic constipation and constipation-predominant irritable bowel syndrome (IBS-C) by promoting intestinal secretion and transit (PubMed: 2010 review). Beyond its role in fluid regulation, GC-C is also investigated as a biomarker and therapeutic target in colorectal cancer, where its expression is maintained in metastatic cells (MDPI: GC-C as a Pharmacological Target). Additionally, the heat-stable enterotoxin itself is a target for vaccine development aimed at preventing ETEC-mediated diarrheal disease (PMC: ST as a Vaccine Target).

Other names

Heat-stable enterotoxin receptorGuanylyl cyclase CGUCY2CSTARGUC2ChSTARIntestinal guanylate cyclaseSTa receptorHeat-stable enterotoxin

Agonism of the receptor leads to increased intracellular cyclic GMP (cGMP), which activates protein kinase G II (PKG-II) and inhibits phosphodiesterase 3 (PDE3). This results in the activation of the cystic fibrosis transmembrane conductance regulator (CFTR) and inhibition of the sodium-hydrogen exchanger 3 (NHE3), promoting the secretion of chloride and bicarbonate and inhibiting sodium absorption, which collectively drive fluid secretion into the intestinal lumen.