Guanylate cyclase C (GUCY2C) (GUCY2C)

Guanylate cyclase C (GUCY2C) is a transmembrane receptor enzyme primarily localized to the apical membrane of intestinal epithelial cells (UniProt P25092). It serves as the receptor for endogenous peptides guanylin and uroguanylin, as well as heat-stable enterotoxins produced by bacteria (PubMed: 26303390). Activation of the GUCY2C extracellular domain stimulates the production of intracellular cyclic GMP (cGMP), which in turn activates the cystic fibrosis transmembrane conductance regulator (CFTR) to promote fluid and electrolyte secretion into the intestinal lumen (PubMed: 23733520). Beyond its role in homeostasis, GUCY2C is a prominent therapeutic target in oncology because it is highly expressed in nearly all cases of metastatic colorectal cancer, while its normal expression is sequestered on the mucosal side of the intestinal barrier, providing a privileged site for targeted therapies (PubMed: 27105740). Current clinical applications include agonists like linaclotide for treating irritable bowel syndrome with constipation and the development of antibody-drug conjugates and CAR-T therapies for colorectal cancer (ClinicalTrials.gov).

Other names

Guanylyl cyclase CHeat-stable enterotoxin receptorGC-CGUC2CSTARGuanylate cyclase 2C

Agonism of the extracellular domain to increase intracellular cGMP for gastrointestinal motility; Targeted cell killing via antibody-drug conjugates or CAR-T cells recognizing the extracellular domain.