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1 The Water and Salt Research Center, University of Aarhus, Aarhus, Denmark
2 Department of Woman and Child Health, Karolinska Insitutet, Stockholm, Sweden
* To whom correspondence should be addressed. E-mail: sn{at}ana.au.dk.
The present study examined the role of Protein Kinase A (PKA) and serine256 (S256) phosphorylation for AQP2 trafficking and recycling using AQP2 wild type and AQP2 mutant transfected cells and high resolution confocal microscopical techniques. In transiently transfected MDCK-C4 cells, stimulation with forskolin induced translocation of AQP2 wildtype (AQP2-WT) to the plasma membrane. Treatment of AQP2-WT cells with the PKA inhibitor H89 following forskolin stimulation resulted in internalization of AQP2-WT. Moreover, H89 treatment of AQP2-S256D (mimicking constitutively phosphorylated AQP2 and hence localized to the plasma membrane) resulted in redistribution of AQP2-S256D to intracellular vesicles, even in the presence of forskolin. Both PGE2 and dopamine stimulation induced endocytosis of AQP2-WT and AQP2-S256D, respectively, in forskolin stimulated cells. Consistent with this, dopamine in presence of vasopressin stimulated endocytosis of AQP2 in slices of rat kidney inner medulla without substantial dephosphorylation. In conclusion these results strongly suggest that 1) S256 phosphorylation is necessary but not sufficient for AQP2 plasma membrane expression, 2) active PKA is required for AQP2 plasma membrane expression, 3) PGE2 and dopamine induce internalization of AQP2 independently of AQP2 dephosphorylation, and 4) preceding activation of cAMP production is necessary for PGE2 and dopamine to cause AQP2 internalization.
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