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Lack of Arginine Vasopressin–Induced Phosphorylation of Aquaporin-2 Mutant AQP2-R254L Explains Dominant Nephrogenic Diabetes Insipidus

Fabrizio de Mattia^*, Paul J.M. Savelkoul^*, Erik-Jan Kamsteeg^*, Irene B.M. Konings^*, Peter van der Sluijs, Rudolf Mallmann, Alexander Oksche^,|| and Peter M.T. Deen^*

^* Department of Physiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; Department of Cell Biology, UMC Utrecht, Utrecht, The Netherlands; Elisabeth-Krankenhaus, Essen, Germany; Institut für Pharmakologie, Charité, Campus Benjamin Franklin, Berlin, Germany; and ^|| Forschungsinstitut fur Molekulare Pharmakologie, Campus Berlin Buch, Berlin, Germany

Address correspondence to: Dr. Peter M.T. Deen, Department of Cell Physiology, Radboud University Nijmegen Medical Center, 160, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Phone: 31-243617347; Fax: 31-243616413; E-mail: p.deen{at}ncmls.ru.nl

Received for publication January 25, 2005. Accepted for publication July 8, 2005.

Water homeostasis in humans is regulated by vasopressin, which induces the translocation of homotetrameric aquaporin-2 (AQP2) water channels from intracellular vesicles to the apical membrane of renal principal cells. For this process, phosphorylation of AQP2 at S256 by cAMP-dependent protein kinase A is thought to be essential. Mutations in the AQP2 gene cause recessive and dominant nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin. Here, a family in which dominant NDI was caused by an exchange of arginine 254 by leucine in the intracellular C terminus of AQP2 (AQP2-R254L), which destroys the protein kinase A consensus site, was identified. Expressed in oocytes, AQP2-R254L appeared to be a functional water channel but was impaired in its transport to the cell surface to the same degree as AQP2-S256A, which mimics nonphosphorylated AQP2. In polarized renal cells, AQP2-R254L was retained intracellularly and was distributed similarly as AQP2-S256A or wild-type AQP2 in unstimulated cells. Upon co-expression in MDCK cells, AQP2-R254L interacted with and retained wild-type AQP2 in intracellular vesicles. Furthermore, AQP2-R254L had a low basal phosphorylation level, which was not increased with forskolin, and mimicking constitutive phosphorylation in AQP2-R254L with the S256D mutation shifted its expression to the basolateral and apical membrane. These data indicate that dominant NDI in this family is due to a R254L mutation, resulting in the loss of arginine vasopressin–mediated phosphorylation of AQP2 at S256, and illustrates the in vivo importance of phosphorylation of AQP2 at S256 for the first time.

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