Receptor guanylyl cyclase C (GC-C): regulation and signal transduction

Abstract

Receptor guanylyl cyclase C (GC-C) is the target for the gastrointestinal hormones, guanylin, and uroguanylin as well as the bacterial heat-stable enterotoxins. The major site of expression of GC-C is in the gastrointestinal tract, although this receptor and its ligands play a role in ion secretion in other tissues as well. GC-C shares the domain organization seen in other members of the family of receptor guanylyl cyclases, though subtle differences highlight some of the unique features of GC-C. Gene knock outs in mice for GC-C or its ligands do not lead to embryonic lethality, but modulate responses of these mice to stable toxin peptides, dietary intake of salts, and development and differentiation of intestinal cells. It is clear that there is much to learn in future about the role of this evolutionarily conserved receptor, and its properties in intestinal and extra-intestinal tissues.

Guanylate cyclase 2C agonism corrects CFTR mutants

“…Hence, it is important to study the mechanisms that benefit GI transit in CF and worth identifying pathways that can be specifically targeted in the GI system without a multisystemic interference in CF. Guanylate cyclase 2C (GCC), the receptor for the endogenous hormones guanylin and uroguanylin and heat-stable enterotoxins from E. coli (STa) is predominantly expressed in intestinal epithelial cells, with no expression reported in other epithelial cell types (5). Activation of GCC results in elevated levels of intracellular cyclic guanosine monophosphate (cGMP), which can stimulate CFTR-mediated chloride ion transport into the intestinal lumen to drive water transit (6)(7)(8)(9).…”

Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis

“…Uroguanylin (UG) and guanylin (GN) activate guanylate cyclase-C (GC-C) receptors expressed on the epithelial cells lining the GI mucosa to stimulate production of cyclic GMP (cGMP), which in turn sequentially activates protein kinase G-Ⅱand cystic fibrosis transmembrane conductance regulator to regulate ion and fluid transport, epithelial cell homeostasis and to maintain barrier function in the GI mucosa [7][8][9][10] . The expression of mRNAs encoding UG and GN are markedly suppressed in human colonic polyps, tumors and in inflamed tissues from UC and CD patients [10][11][12][13] .…”

Simultaneous Exposure to Escherichia coli Heat-Labile and Heat-Stable Enterotoxins Increases Fluid Secretion and Alters Cyclic Nucleotide and Cytokine Production by Intestinal Epithelial Cells

“…The GC-C receptor is a single transmembrane protein receptor with an extracellular domain, a transmembrane domain, a kinase domain, a hinge region, and a guanylate cyclase catalytic domain (17). Upon ST binding to the GC-C extracellular domain, the receptor is internalized (18) and a signal is transduced through the GC-C receptor to the catalytic domain, resulting in an increase in intracellular cyclic GMP (cGMP) levels (19,20).…”