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Published ahead of print on August 24, 2005
Journal of the American Society of Nephrology
© 2005 American Society of Nephrology
doi: 10.1681/ASN.2005010104
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BASIC SCIENCE: Cell and Transport Physiology

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

Fabrizio de Mattia 1, Paul J.M. Savelkoul 1, Erik-Jan Kamsteeg 1, Irene B.M. Konings 1, Peter van der Sluijs 1, Rudolf Mallmann 1, Alexander Oksche 1, Peter M.T. Deen 1*

1

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


* To whom correspondence should be addressed. E-mail: p.deen{at}ncmls.ru.nl.


  Abstract

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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