Aquaporin-2 (AQP2) trafficking to the apical membrane of collecting duct principal cells is regulated by ADH. What is the intracellular signaling pathway?

• A ADH → V1a receptor → Gq → PLC → IP3 → Ca²⁺ → calmodulin → AQP2 insertion
• B ADH → V2 receptor → Gi → decreased cAMP → PKC activation → AQP2 insertion
• C ADH → V2 receptor → Gs → adenylyl cyclase → cAMP → PKA → phosphorylation of AQP2 Ser256 → exocytosis of AQP2-containing vesicles ✓
• D ADH → AT1 receptor → Gq → PKC → AQP2 phosphorylation → apical insertion

Explanation

ADH binds V2 receptors (Gs-coupled) on the basolateral membrane of collecting duct principal cells. Gs activates adenylyl cyclase, raising cAMP, which activates PKA. PKA phosphorylates AQP2 at serine 256, triggering vesicular exocytosis and insertion of AQP2 channels into the apical membrane. Water then moves transcellularly via AQP2 (apical) and AQP3/4 (basolateral) channels into the hypertonic medullary interstitium, concentrating urine. In nephrogenic DI, V2 receptor or AQP2 mutations prevent this signaling cascade.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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