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J. Biol. Chem., Vol. 280, Issue 20, 19875-19882, May 20, 2005

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Identification of an Endogenous Inhibitor of the Cardiac Na⁺/Ca²⁺ Exchanger, Phospholemman^*

Belinda A. Ahlers, Xue-Qian Zhang, J. Randall Moorman¶, Lawrence I. Rothblum, Lois L. Carl, Jianliang Song, JuFang Wang, Lisa M. Geddis¶, Amy L. Tucker¶, J. Paul Mounsey¶, and Joseph Y. Cheung||

From the Department of Cellular and Molecular Physiology and ^||Department of Medicine, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania 17033, Weis Center for Research, Geisinger Medical Center, Danville, Pennsylvania 17822, and ^¶Department of Internal Medicine (Cardiovascular Division), University of Virginia Health Sciences Center, Charlottesville, Virginia 22908

Rapid and precise control of Na⁺/Ca²⁺ exchanger (NCX1) activity is essential in the maintenance of beat-to-beat Ca²⁺ homeostasis in cardiac myocytes. Here, we show that phospholemman (PLM), a 15-kDa integral sarcolemmal phosphoprotein, is a novel endogenous protein inhibitor of cardiac NCX1. Using a heterologous expression system that is devoid of both endogenous PLM and NCX1, we first demonstrated by confocal immunofluorescence studies that both exogenous PLM and NCX1 co-localized at the plasma membrane. Reciprocal co-immunoprecipitation studies revealed specific protein-protein interaction between PLM and NCX1. The functional consequences of direct association of PLM with NCX1 was the inhibition of NCX1 activity, as demonstrated by whole-cell patch clamp studies to measure NCX1 current density and radiotracer flux assays to assess Na⁺-dependent ⁴⁵Ca²⁺ uptake. Inhibition of NCX1 by PLM was specific, because a single mutation of serine 68 to alanine in PLM resulted in a complete loss of inhibition of NCX1 current, although association of the PLM mutant with NCX1 was unaltered. In native adult cardiac myocytes, PLM co-immunoprecipitated with NCX1. We conclude that PLM, a member of the FXYD family of small ion transport regulators known to modulate Na⁺-K⁺-ATPase, also regulates Na⁺/Ca²⁺ exchange in the heart.

Received for publication, December 30, 2004 , and in revised form, February 28, 2005.

^* This work was supported in part by the National Institutes of Health Grants HL-58672 (to J. Y. C.), DK-46678 (to J. Y. C.), HL-70548 and GM-64640 (to J. R. M.), HL-69074 (to A. L. T.), American Heart Association Pennsylvania Affiliate Grants-in-aid for scientific research 0265426U (to X.-Q. Z.) and 0355744U (to J. Y. C.), American Heart Association Pennsylvania Affiliate Post-Doctoral Fellowship 0425319U (to B. A. A.), and by grants from the Geisinger Foundation (to J. Y. C. and L. I. 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.

To whom correspondence should be addressed: Dept. of Cellular and Molecular Physiology, Milton S. Hershey Medical Center, MC-H166, Hershey, PA 17033. Tel.: 717-531-5748; Fax: 717-531-7667; E-mail: jyc1{at}psu.edu.

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