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J. Biol. Chem., Vol. 280, Issue 33, 29479-29487, August 19, 2005

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The Sarcolemmal Calcium Pump Inhibits the Calcineurin/Nuclear Factor of Activated T-cell Pathway via Interaction with the Calcineurin A Catalytic Subunit^*

Mamta H. Buch, Adam Pickard, Antonio Rodriguez¶, Sheona Gillies, Alexander H. Maass||, Michael Emerson, Elizabeth J. Cartwright, Judith C. Williams, Delvac Oceandy, Juan M. Redondo¶, Ludwig Neyses**, and Angel L. Armesilla**

From the Division of Cardiology, The University of Manchester, Stopford Bldg., Oxford Road, Manchester M13 9PT, United Kingdom, the ^¶Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid 28049, Spain, and the ^||Department of Medicine, University of Wuerzburg, Wuerzburg 97080, Germany

The calcineurin/nuclear factor of activated T-cell (NFAT) pathway represents a crucial transducer of cellular function. There is increasing evidence placing the sarcolemmal calcium pump, or plasma membrane calcium/calmodulin ATPase pump (PMCA), as a potential modulator of signal transduction pathways. We demonstrate a novel interaction between PMCA and the calcium/calmodulin-dependent phosphatase, calcineurin, in mammalian cells. The interaction domains were located to the catalytic domain of PMCA4b and the catalytic domain of the calcineurin A subunit. Endogenous calcineurin activity, assessed by measuring the transcriptional activity of its best characterized substrate, NFAT, was significantly inhibited by 60% in the presence of ectopic PMCA4b. This inhibition was notably reversed by the co-expression of the PMCA4b interaction domain, demonstrating the functional significance of this interaction. PMCA4b was, however, unable to confer its inhibitory effect in the presence of a calcium/calmodulin-independent constitutively active mutant calcineurin A suggesting a calcium/calmodulin-dependent mechanism. The modulatory function of PMCA4b is further supported by the observation that endogenous calcineurin moves from the cytoplasm to the plasma membrane when PMCA4b is overexpressed. We suggest recruitment by PMCA4b of calcineurin to a low calcium environment as a possible explanation for these findings. In summary, our results offer strong evidence for a novel functional interaction between PMCA and calcineurin, suggesting a role for PMCA as a negative modulator of calcineurin-mediated signaling pathways in mammalian cells. This study reinforces the emerging role of PMCA as a molecular organizer and regulator of signaling transduction pathways.

Received for publication, February 4, 2005 , and in revised form, June 9, 2005.

^* This work was supported in part by the Medical Research Council (International Appointee Grant G0200020 to L. N.) and by the Deutsche Forschungsgemeinschaft (Grant Ma2185/1-1 to A. H. M., Grant SAF2003-02920 to J. M. R., and Grant FIS-031474 to A. R.). 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.

A recipient of a Wellcome Trust entry-level training fellowship.

^** Equal senior authors.

To whom correspondence should be addressed. Tel.: 44-161-276-5738; Fax: 44-161-276-5669; E-mail: ludwig.neyses{at}cmmc.nhs.uk.

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