Heat-stable enterotoxin receptor (GUCY2C, STAR) is the receptor for the endogenous peptides guanylin (GUCA2A) and uroguanylin (GUCA2B) and E.coli heat-stable enterotoxin (sta1). GUCY2C is an integral membrane protein composed of an extracellular ligand-binding domain, an intracellular domain and a guanylyl cyclase catalytic domain and functions in trimeric form (Vijayachandra et al. 2000). Once activated by its ligands, GUCY2C mediates fluid-ion homeostasis, intestinal inflammation, and cell proliferation in a cGMP-dependent manner (Arshad et al. 2013). In the intestine, E.coli heat-stable enterotoxin (sta1) binding to GUCY2C causes abnormally high levels of intracellular cGMP to be produced resulting in aberrant fluid-ion efflux, leading to secretory diarrhea, the leading cause of infectious diarrhea in humans (Basu et al. 2010, Kopic & Geibel 2010). GUCY2C requires glycosylation for correct ligand binding and cell-surface localisation. When glycosylation is prevented in systematic mutagenesis studies, both ligand binding and localisation were abolished (Arshad et al. 2013).
Na(+)/H(+) exchange regulatory cofactor NHE-RF4 (PDZD3, aka IKEPP, NHERF4) is a regulatory protein that associates with GUCY2C and negatively modulates its heat-stable enterotoxin-mediated activation. PDZD3 is expressed in the intestinal epithelium, where it preferentially accumulates at the apical surface, and there associates with the COOH terminus of GUCY2C (Scott et al. 2002).