Guanylate cyclase 2C (GUCY2C) (GUCY2C)

Guanylate cyclase 2C (GUCY2C), also known as the heat-stable enterotoxin receptor, is a transmembrane receptor primarily expressed on the apical surface of intestinal epithelial cells [1, 5]. Its extracellular domain serves as the binding site for endogenous ligands such as guanylin and uroguanylin, as well as bacterial heat-stable enterotoxins [1, 10]. Upon ligand binding to the extracellular domain, the intracellular catalytic domain is activated, converting GTP into cyclic GMP (cGMP) [7, 11]. This second messenger regulates fluid and electrolyte homeostasis by activating the cystic fibrosis transmembrane conductance regulator (CFTR) and inhibiting the sodium-hydrogen exchanger 3 (NHE3) [8, 12]. In clinical medicine, GUCY2C is a major therapeutic target for gastrointestinal disorders like irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC), where agonists like linaclotide and plecanatide are used to increase intestinal secretion and motility [10, 11]. Beyond its role in fluid balance, GUCY2C acts as a tumor suppressor in the intestine, and its expression is a highly specific biomarker for metastatic colorectal cancer [7, 16]. Novel therapies, including antibody-drug conjugates and CAR-T cells, are currently being developed to target the GUCY2C extracellular domain in oncology [14, 16].

Other names

Guanylyl cyclase CGC-CHeat-stable enterotoxin receptorhSTARIntestinal guanylate cyclaseSTARGUC2CGCC

Agonism of the extracellular domain activates the intracellular catalytic domain, increasing cyclic GMP (cGMP) levels, which regulates fluid secretion and cell homeostasis.