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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 α1-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.

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}

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