Guanylate cyclase 2C

Guanylate Cyclase 2C (GC-C or GUCY2C) is an enzyme that in humans is encoded by the GUCY2C gene. This membrane-bound enzyme is a part of the guanylate cyclase family, which plays a crucial role in the regulation of electrolyte and water transport in intestinal and renal epithelia. Activation of GC-C results in the production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP), a process that is essential for mediating the effects of endogenous ligands such as guanylin and uroguanylin, as well as the diarrheagenic bacterial heat-stable enterotoxins.

Function

GC-C is predominantly expressed in the intestinal epithelium, where it regulates fluid and electrolyte secretion and absorption. This regulation is vital for maintaining the balance of water and salts in the body, a key aspect of homeostasis. The enzyme is activated by its ligands, leading to an increase in intracellular cGMP levels. This elevation in cGMP activates cGMP-dependent protein kinase II (PKG II), which subsequently phosphorylates the cystic fibrosis transmembrane conductance regulator (CFTR) and other proteins involved in the regulation of ion channels and transporters. Through these mechanisms, GC-C plays a significant role in the pathophysiology of various gastrointestinal disorders, including secretory diarrheas and inflammatory bowel disease (IBD).

Clinical Significance

The role of GC-C in the gastrointestinal system has made it a target for therapeutic intervention. Linaclotide and plecanatide, two drugs that mimic the effects of endogenous GC-C ligands, have been approved for the treatment of irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC). These medications work by activating GC-C, which increases cGMP levels, leading to enhanced secretion of chloride and bicarbonate into the intestinal lumen, improving bowel movements and alleviating symptoms associated with constipation.

Furthermore, the expression of GC-C has been explored as a biomarker for colorectal cancer (CRC) since it is highly expressed in the intestinal epithelium and its expression decreases in CRC. Research into the role of GC-C and its ligands in tumorigenesis is ongoing, with the potential for developing novel diagnostic and therapeutic strategies targeting this pathway.

Genetics

The GUCY2C gene is located on chromosome 12p12.3 and consists of 23 exons. Mutations in this gene have been associated with familial GUCY2C diarrhea syndrome, a rare autosomal dominant disorder characterized by chronic diarrhea and intestinal malabsorption.

See Also

• cGMP
• CFTR
• PKG
• IBS
• CRC

References

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