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J. Biol. Chem. 278 (50): 50355-50361

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Cell Signaling Microdomain with Na,K-ATPase and Inositol 1,4,5-Trisphosphate Receptor Generates Calcium Oscillations*

Ayako Miyakawa-Naito{ddagger}, Per Uhlén{ddagger}, Mark Lal, Oleg Aizman, Katsuhiko Mikoshiba§, Hjalmar Brismar, Sergey Zelenin, , and Anita Aperia¶

Department of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, S-171 76 Stockholm, Sweden and the §Department of Basic Medical Science, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan

Abstract: Recent studies indicate novel roles for the ubiquitous ion pump, Na,K-ATPase, in addition to its function as a key regulator of intracellular sodium and potassium concentration. We have previously demonstrated that ouabain, the endogenous ligand of Na,K-ATPase, can trigger intracellular Ca2+ oscillations, a versatile intracellular signal controlling a diverse range of cellular processes. Here we report that Na,K-ATPase and inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R) form a cell signaling microdomain that, in the presence of ouabain, generates slow Ca2+ oscillations in renal cells. Using fluorescent resonance energy transfer (FRET) measurements, we detected a close spatial proximity between Na,K-ATPase and InsP3R. Ouabain significantly enhanced FRET between Na,K-ATPase and InsP3R. The FRET effect and ouabain-induced Ca2+ oscillations were not observed following disruption of the actin cytoskeleton. Partial truncation of the NH2 terminus of Na,K-ATPase catalytic {alpha}1-subunit abolished Ca2+ oscillations and downstream activation of NF-{kappa}B. Ouabain-induced Ca2+ oscillations occurred in cells expressing an InsP3 sponge and were hence independent of InsP3 generation. Thus, we present a novel principle for a cell signaling microdomain where an ion pump serves as a receptor.

Received for publication May 22, 2003. Revision received August 20, 2003.

* This work was supported by grants from the Swedish Research Council, the Persson Family Foundation, the Märta and Gunnar V. Philipson Foundation (to A. A. and H. B.), Japan Science and Technology Corporation "Calcium Oscillation Project" (to K. M. and A. A.), and the Ministry of Education, Science, Sports and Culture of Japan (to A. M.-N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{ddagger} Both authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, Q2:09, S-171 76 Stockholm, Sweden. Tel.: 46-8-51777326; Fax: 46-8-51777328; E-mail: anita.aperia{at}ks.se.

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