Guanylyl cyclase C (GUCY2C) (GUCY2C)

Guanylyl cyclase C (GUCY2C) is a transmembrane receptor primarily expressed on the apical surface of intestinal epithelial cells from the duodenum to the rectum [UniProt: P25092]. It functions as a key regulator of intestinal fluid and electrolyte homeostasis by converting GTP to cyclic GMP (cGMP) upon activation by endogenous ligands like guanylin and uroguanylin, or exogenous heat-stable enterotoxins [PubMed: 25614205]. This increase in cGMP activates the cystic fibrosis transmembrane conductance regulator (CFTR) and inhibits the sodium-hydrogen exchanger 3 (NHE3), resulting in increased secretion of chloride and bicarbonate into the intestinal lumen and subsequent fluid movement [StatPearls: NBK538254]. Beyond its role in secretion, GUCY2C signaling is involved in maintaining the intestinal mucosal barrier and regulating epithelial cell proliferation and differentiation [PubMed: 23434910]. In clinical practice, GUCY2C is a validated therapeutic target for gastrointestinal disorders such as chronic idiopathic constipation and irritable bowel syndrome with constipation, where agonists like linaclotide are used to improve bowel movement frequency and reduce visceral pain [FDA: Linaclotide Label]. Furthermore, GUCY2C is highly expressed in primary and metastatic colorectal cancer while remaining restricted to the intestinal mucosa in healthy tissue, making it a promising biomarker and target for immunotherapies, including CAR-T cells and antibody-drug conjugates [PubMed: 27103502].

Other names

Guanylate cyclase 2CHeat-stable enterotoxin receptorGCCGUC2CSTARGuanylate cyclase C

Agonism of the extracellular domain triggers intracellular conversion of GTP to cGMP, leading to activation of CFTR and inhibition of NHE3, which increases intestinal fluid secretion and accelerates transit [PubMed: 25614205, StatPearls: NBK538254].