Diabetes insipidus (DI) is characterised by the inability to concentrate urine. Central DI results from ADH (vasopressin) deficiency; nephrogenic DI results from resistance to ADH. ADH acts on principal cells of the collecting duct via V2 receptor coupled to Gs. The intracellular signalling pathway that leads to insertion of aquaporin-2 (AQP2) into the apical membrane is:

• A V2 → Gq → PLC → IP3 → Ca2+ → calmodulin kinase → AQP2 membrane insertion
• B V2 → Gi → reduced cAMP → PKC activation → AQP2 phosphorylation
• C V2 → Gs → adenylate cyclase → cAMP → PKA → phosphorylation of AQP2 Ser256 → vesicle fusion ✓
• D V2 → JAK2 → STAT5 → AQP2 gene transcription only (no acute effect)

Explanation

ADH binds V2 receptor (basolateral membrane of principal cells) coupled to Gs. Gs activates adenylate cyclase → cAMP → PKA (protein kinase A). PKA phosphorylates AQP2 at Ser256 (short-term regulation), causing intracellular AQP2-containing vesicles to fuse with the apical plasma membrane, dramatically increasing water permeability. Long-term ADH exposure also increases AQP2 gene expression. AQP3 and AQP4 are constitutively expressed on the basolateral membrane. In nephrogenic DI, AVPR2 (V2 receptor, X-linked) or AQP2 gene mutations prevent this signalling. Treatment of nephrogenic DI includes thiazide diuretics (paradoxical concentration) and NSAIDs (reducing prostaglandin-mediated inhibition of the cAMP pathway).

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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