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Reciprocal interaction with G-actin and tropomyosin is essential for aquaporin-2 trafficking

¹ Department of Nephrology and ² COE Program for Brain Integration and its Disorders, Graduate School of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
³ Division of Pathophysiology and ⁴ Department of Autonomic Physiology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, 113-8510 Japan
⁵ Laboratory of Supramolecular Biophysics, Research Institute for Electronic Science, Hokkaido University, N12W6, Kita-Ku, Sapporo 060-0812, Japan
⁶ Department of Cellular Neurobiology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan

Correspondence to Yumi Noda: ynodmed2{at}tmd.ac.jp

Trafficking of water channel aquaporin-2 (AQP2) to the apical membrane and its vasopressin and protein kinase A (PKA)–dependent regulation in renal collecting ducts is critical for body water homeostasis. We previously identified an AQP2 binding protein complex including actin and tropomyosin-5b (TM5b). We show that dynamic interactions between AQP2 and the actin cytoskeleton are critical for initiating AQP2 apical targeting. Specific binding of AQP2 to G-actin in reconstituted liposomes is negatively regulated by PKA phosphorylation. Dual color fluorescence cross-correlation spectroscopy reveals local AQP2 interaction with G-actin in live epithelial cells at single-molecule resolution. Cyclic adenosine monophosphate signaling and AQP2 phosphorylation release AQP2 from G-actin. In turn, AQP2 phosphorylation increases its affinity to TM5b, resulting in reduction of TM5b bound to F-actin, subsequently inducing F-actin destabilization. RNA interference–mediated knockdown and overexpression of TM5b confirm its inhibitory role in apical trafficking of AQP2. These findings indicate a novel mechanism of channel protein trafficking, in which the channel protein itself critically regulates local actin reorganization to initiate its movement.

© 2008 Noda et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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• Hoffert, J. D., Chou, C.-L., Knepper, M. A. (2009). Aquaporin-2 in the "-omics" Era. J. Biol. Chem. 284: 14683-14687 [Abstract] [Full Text]  
• Nunes, P., Hasler, U., McKee, M., Lu, H. A. J., Bouley, R., Brown, D. (2008). A fluorimetry-based ssYFP secretion assay to monitor vasopressin-induced exocytosis in LLC-PK1 cells expressing aquaporin-2. Am. J. Physiol. Cell Physiol. 295: C1476-C1487 [Abstract] [Full Text]  
• Robinson, R. (2008). Aquaporin clears its own path. JCB 182: 412-413 [Full Text]  

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