Compartmentalization of cAMP-Dependent Signaling by Phosphodiesterase-4D Is Involved in the Regulation of Vasopressin-Mediated Water Reabsorption in Renal Principal Cells
Journal of the American Society of Nephrology
The cAMP/protein kinase A (PKA)-dependent insertion of water channel aquaporin-2 (AQP2)-bearing vesicles into the plasma membrane in renal collecting duct principal cells (AQP2 shuttle) constitutes the molecular basis of arginine vasopressin (AVP)-regulated water reabsorption. cAMP/PKA signaling systems are compartmentalized by A kinase anchoring proteins (AKAP) that tether PKA to subcellular sites and by phosphodiesterases (PDE) that terminate PKA signaling through hydrolysis of localized
... s of localized cAMP. In primary cultured principal cells, AVP causes focal activation of PKA. PKA and cAMPspecific phosphodiesterase-4D (PDE4D) are located on AQP2-bearing vesicles. The selective PDE4 inhibitor rolipram increases AKAP-tethered PKA activity on AQP2-bearing vesicles and enhances the AQP2 shuttle and thereby the osmotic water permeability. AKAP18␦, which is located on AQP2-bearing vesicles, directly interacts with PDE4D and PKA. In response to AVP, PDE4D and AQP2 translocate to the plasma membrane. Here PDE4D is activated through PKA phosphorylation and reduces the osmotic water permeability. Taken together, a novel, compartmentalized, and physiologically relevant cAMPdependent signal transduction module on AQP2-bearing vesicles, comprising anchored PDE4D, AKAP18␦, and PKA, has been identified. A ntidiuretic hormone (arginine vasopressin [AVP]) induces fusion of vesicles that contain the water channel aquaporin-2 (AQP2) with the plasma membrane of renal collecting duct principal cells. This "AQP2 shuttle" increases the osmotic water permeability (Pf) of the cells, facilitating water reabsorption from the collecting duct (1). The AQP2 shuttle is initiated upon binding of AVP to vasopressin-2 receptors (V2R) and triggered by the consequent cAMP elevation and protein kinase A (PKA) activation. It is the PKA phosphorylation of AQP2 that elicits redistribution of AQP2-bearing vesicles. Pivotal to this redistribution is the compartmentalization of PKA by A kinase anchoring proteins (AKAP) (2). Phosphodiesterases (PDE), which are the sole means of degrading cAMP, are poised to regulate PKA signaling (3-6). The PDE4 family has attracted great interest because of its link to stroke (7), schizophrenia (8), and the therapeutic potential of selective inhibitors for treating inflammatory diseases (9-12). The four subfamilies (PDE4A through D) are encoded by separate genes, generating approximately 20 isoforms (9,11) that can interact with scaffolding proteins, including AKAP and ␤-arrestin (12-16), positioning them for a role in compartmentalized cAMP/PKA signaling. Here we show that compartmentalization of cAMP/PKA signaling by PDE4 is involved in the regulation of the AQP2 shuttle and the Pf. This is of particular pertinence because PDE4 hyperactivity causes nephrogenic diabetes insipidus in a mouse model (17).