A patient with a VIPoma (Verner-Morrison syndrome) presents with profuse watery diarrhoea, hypokalaemia, and achlorhydria. VIP (vasoactive intestinal peptide) mediates this via which intracellular mechanism in intestinal crypt cells?
- A VIP binds VPAC1/VPAC2 receptors (Gs-coupled) on crypt colonocytes, elevating cAMP via adenylyl cyclase, which activates PKA; PKA phosphorylates and activates the CFTR Cl⁻ channel, driving Cl⁻ secretion into the lumen with obligate Na⁺ and water following paracellularly ✓
- B VIP activates Gq-PLC on colonocytes, generating IP3 that releases Ca²⁺ from the ER; Ca²⁺ opens Ca²⁺-activated K⁺ channels and indirectly drives Cl⁻ secretion
- C VIP stimulates enteric cholinergic neurons to release acetylcholine, which activates M3 receptors on enterocytes to increase Na⁺ secretion via ENaC reversal
- D VIP activates guanylate cyclase C (GC-C) on enterocytes, raising cGMP and inhibiting the NHE3 Na-H exchanger, preventing Na⁺ absorption and causing osmotic diarrhoea
Explanation
VIP binds VPAC1/VPAC2 G-protein-coupled receptors that couple to Gs → adenylyl cyclase → cAMP → PKA. PKA phosphorylates CFTR (cystic fibrosis transmembrane conductance regulator) Cl⁻ channels on the apical membrane, activating Cl⁻ secretion into the intestinal lumen. Lumen-negative potential and elevated luminal osmolality then drive paracellular Na⁺ secretion and osmotic water loss — producing the massive secretory diarrhoea. This is the same cAMP-PKA-CFTR mechanism used by cholera toxin (via ADP-ribosylation of Gs-alpha). Option D describes the GC-C pathway used by heat-stable enterotoxin (STa) and linaclotide (cGMP-mediated). Option B (Gq/Ca²⁺) is not the primary VIP pathway.
Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.
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