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J. Biol. Chem., Vol. 281, Issue 12, 7784-7792, March 24, 2006

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Phospholemman Inhibition of the Cardiac Na⁺/Ca²⁺ Exchanger

ROLE OF PHOSPHORYLATION^*

Xue-Qian Zhang, Belinda A. Ahlers, Amy L. Tucker, Jianliang Song, JuFang Wang, J. Randall Moorman, J. Paul Mounsey, Lois L. Carl, Lawrence I. Rothblum^¶, and Joseph Y. Cheung^||1

From the Departments of Cellular and Molecular Physiology and ^||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

We have demonstrated previously that phospholemman (PLM), a 15-kDa integral sarcolemmal phosphoprotein, inhibits the cardiac Na⁺/Ca²⁺ exchanger (NCX1). In addition, protein kinase A phosphorylates serine 68, whereas protein kinase C phosphorylates both serine 63 and serine 68 of PLM. Using human embryonic kidney 293 cells that are devoid of both endogenous PLM and NCX1, we first demonstrated that the exogenous NCX1 current (I_NaCa) was increased by phorbol 12-myristate 13-acetate (PMA) but not by forskolin. When co-expressed with NCX1, PLM resulted in: (i) decreases in I_NaCa, (ii) attenuation of the increase in I_NaCa by PMA, and (iii) additional reduction in I_NaCa in cells treated with forskolin. Mutating serine 63 to alanine (S63A) preserved the sensitivity of PLM to forskolin in terms of suppression of I_NaCa, whereas mutating serine 68 to alanine (S68A) abolished the inhibitory effect of PLM on I_NaCa. Mutating serine 68 to glutamic acid (phosphomimetic) resulted in additional suppression of I_NaCa as compared with wild-type PLM. These results suggest that PLM phosphorylated at serine 68 inhibited I_NaCa. The physiological significance of inhibition of NCX1 by phosphorylated PLM was evaluated in PLM-knock-out (KO) mice. When compared with wild-type myocytes, I_NaCa was significant larger in PLM-KO myocytes. In addition, the PMA-induced increase in I_NaCa was significantly higher in PLM-KO myocytes. By contrast, forskolin had no effect on I_NaCa in wild-type myocytes. We conclude that PLM, when phosphorylated at serine 68, inhibits Na⁺/Ca²⁺ exchange in the heart.

Received for publication, November 9, 2005 , and in revised form, January 17, 2006.

^* This work was supported in part by National Institutes of Health Grants HL-58672 and HL-74854 (to J. Y. C.), DK-46678 (to J. Y. C., co-investigator), GM-69841 (to L. I. R.), HL-70548 and GM-64640 (to J. R. M.), and HL-69074 (to A. L. T.); American Heart Association Pennsylvania Affiliate Grants-in-aid 0265426U (to X.-Q. Z.) and 0355744U (to J. Y. C.); American Heart Association Pennsylvania Affiliate Postdoctoral Fellowship 0425319U (to B. A. A.); and 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.

¹ 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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