Guanylate cyclase 2C receptor (GC-C (also GUCY2C))

Guanylate cyclase 2C receptor is a transmembrane enzyme-receptor predominantly expressed on the luminal surface of intestinal epithelial cells. It serves as the physiological target for endogenous peptide hormones guanylin and uroguanylin, as well as bacterial heat-stable enterotoxins responsible for certain diarrheal illnesses. Upon ligand binding, it catalyzes conversion of GTP into cyclic GMP—a second messenger that regulates key processes such as fluid/electrolyte secretion via activation of CFTR channels. This pathway maintains gut homeostasis by controlling hydration/secretion balance, supporting epithelial renewal/barrier function, modulating inflammation, and suppressing tumorigenesis. Dysregulation or mutation leads to various gastrointestinal diseases including chronic constipation syndromes when underactive or secretory diarrheas when overactive. The receptor remains highly expressed in most colorectal cancers even after malignant transformation—making it both an attractive therapeutic target for small-molecule agonists/antagonists and immunotherapies like CAR-T cells—and a clinically useful biomarker for detecting metastatic disease spread beyond the colon.[1][4][5][6][9]

Other names

Guanylyl cyclase CIntestinal guanylate cyclaseGuanylate cyclase-C receptorHeat-stable enterotoxin receptor (hSTAR)GUCY2C

Agonists such as linaclotide and plecanatide bind to GC-C, activating the receptor to catalyze cGMP production from GTP, which then activates downstream signaling pathways that increase chloride and water secretion into the intestine by stimulating CFTR channels, improving bowel movement frequency and consistency in constipation disorders.[6][7] – CAR-T cells engineered to target GC-C recognize tumor cells expressing this antigen and mediate cytotoxicity against them.[3]