Linaclotide

Linaclotide is a potent, highly selective agonist of guanylate cyclase-C (GC-C), a soluble and single-membrane-spanning enzyme on the luminal surface of intestinal epithelial cells. GC-C regulates chloride secretion. Linaclotide has a dual mode of action. Firstly, linaclotide and its active metabolite bind to transmembrane GC-C. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevated intracellular cGMP activates the cGMP-dependent protein kinase II (PKG-II), which phosphorylates and activates the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel expressed on the apical surface of intestinal epithelial cells. CFTR activation promotes the secretion of chloride and bicarbonate ions and inhibits sodium absorption, resulting in increased intestinal fluid and accelerated GI transit.

Secondly, linaclotide exerts anti-nociceptive effects by reducing visceral hypersensitivity. Increased levels of extracellular cGMP in submucosa inhibit colonic nociceptors, relieving intestinal pain.