Guanylyl cyclase C (GC-C) (GC-C)

Guanylyl cyclase C (GC-C) is a transmembrane receptor-enzyme primarily expressed on the apical membrane of intestinal epithelial cells [UniProt P25092]. It functions as the receptor for endogenous peptides guanylin and uroguanylin, as well as heat-stable enterotoxins from bacteria like E. coli [PubMed: 29330227]. Activation of GC-C triggers the conversion of GTP to cyclic GMP (cGMP), which regulates intestinal fluid homeostasis by activating the cystic fibrosis transmembrane conductance regulator (CFTR) and inhibiting the sodium-hydrogen exchanger 3 (NHE3) [StatPearls: Linaclotide]. This process increases the secretion of chloride and bicarbonate into the intestinal lumen, drawing water in and accelerating gastrointestinal transit [PubMed: 25101017]. Beyond fluid regulation, GC-C signaling plays a role in maintaining the intestinal barrier and suppressing epithelial cell proliferation, making it a target for colorectal cancer research [PubMed: 26895557]. Therapeutic agonists such as linaclotide and plecanatide are clinically used to treat irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) [FDA: Linzess Label].

Other names

Guanylate cyclase 2CGUCY2CHeat-stable enterotoxin receptorSTARGUC2CGuanylate cyclase C

Agonist binding to the extracellular domain of Guanylyl cyclase C stimulates its intracellular catalytic domain to convert GTP to cyclic GMP (cGMP). The resulting increase in intracellular cGMP activates protein kinase G-II (PKG-II), which phosphorylates and opens the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. This leads to the secretion of chloride and bicarbonate into the intestinal lumen, followed by passive water movement, which increases intestinal fluid and accelerates transit [PubMed: 25101017, StatPearls: Linaclotide].