title: Compartmentalization of cAMP-dependent signaling by phosphodiesterase-4D is involved in the regulation of vasopressin-mediated water reabsorption in renal principal cells.
abstract: 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 cAMP. In primary cultured principal cells, AVP causes focal activation of PKA. PKA and cAMP-specific 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. AKAP18delta, 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 cAMP-dependent signal transduction module on AQP2-bearing vesicles, comprising anchored PDE4D, AKAP18delta, and PKA, has been identified.
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Eduard
authors.initials: E
authors.lastname: Stefan
authors.forename: Burkhard
authors.initials: B
authors.lastname: Wiesner
authors.forename: George S
authors.initials: GS
authors.lastname: Baillie
authors.forename: Rustam
authors.initials: R
authors.lastname: Mollajew
authors.forename: Volker
authors.initials: V
authors.lastname: Henn
authors.forename: Dorothea
authors.initials: D
authors.lastname: Lorenz
authors.forename: Jens
authors.initials: J
authors.lastname: Furkert
authors.forename: Katja
authors.initials: K
authors.lastname: Santamaria
authors.forename: Pavel
authors.initials: P
authors.lastname: Nedvetsky
authors.forename: Christian
authors.initials: C
authors.lastname: Hundsrucker
authors.forename: Michael
authors.initials: M
authors.lastname: Beyermann
authors.forename: Eberhard
authors.initials: E
authors.lastname: Krause
authors.forename: Peter
authors.initials: P
authors.lastname: Pohl
authors.forename: Irene
authors.initials: I
authors.lastname: Gall
authors.forename: Andrew N
authors.initials: AN
authors.lastname: MacIntyre
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bachmann
authors.forename: Miles D
authors.initials: MD
authors.lastname: Houslay
authors.forename: Walter
authors.initials: W
authors.lastname: Rosenthal
authors.forename: Enno
authors.initials: E
authors.lastname: Klussmann
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D001127:Arginine Vasopressin / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006801:Humans; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020889:Rolipram / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014867:Water / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D010726:Phosphodiesterase Inhibitors; D011994:Recombinant Proteins; D014867:Water; D001127:Arginine Vasopressin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human; D020889:Rolipram