Linaclotide relieves constipation-predominant IBS through a signalling cascade initiated at the luminal surface of intestinal epithelium. The correct sequence is:
- A Activation of guanylate cyclase-C, raised intracellular cGMP, increased chloride and bicarbonate secretion via CFTR ✓
- B Activation of EP4 prostaglandin receptors, raised cAMP, opening of calcium-activated potassium channels
- C Blockade of epithelial sodium channels, osmotic retention of water in the lumen
- D Stimulation of enteric 5-HT4 receptors, acetylcholine release, enhanced peristalsis alone
Correct answer: A. Activation of guanylate cyclase-C, raised intracellular cGMP, increased chloride and bicarbonate secretion via CFTR
Explanation
Linaclotide is a peptide agonist of guanylate cyclase-C on the brush border of intestinal epithelial cells, mimicking the endogenous hormones guanylin and uroguanylin. Raised cGMP activates CFTR, driving chloride and bicarbonate-rich fluid secretion into the lumen, and also reduces visceral pain signalling via cGMP-dependent protein kinase. It is minimally absorbed and acts purely luminally. It does not act through prostaglandin receptors, sodium channel blockade, or serotonergic prokinetic pathways.
Reference: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 14th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.