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M512092200v1
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Papers In Press, published online ahead of print January 23, 2006
J. Biol. Chem, 10.1074/jbc.M512092200
Submitted on November 9, 2005
Revised on January 17, 2006
Accepted on January 22, 2006

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

Cellular & Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033

Corresponding Author: jyc1{at}psu.edu

We have previously demonstrated that phospholemman (PLM), a 15 kDa integral sarcolemmal phosphoprotein, inhibits the cardiac Na+/Ca2+ exchanger (NCX1). In addition, protein kinase A phosphorylates serine68 while protein kinase C phosphorylates both serine63 and serine68 of PLM. Using HEK293 cells that are devoid of both endogenous PLM and NCX1, we first demonstrated that the exogenous NCX1 current (INaCa) was increased by phorbol 12-myristate 13-acetate (PMA) but not by forskolin. When co-expressed with NCX1, PLM resulted in: (i) decreases in INaCa; (ii) attenuation of the increase in INaCa by PMA; and (iii) additional reduction in INaCa in cells treated with forskolin. Mutating serine63 to alanine (S63A) preserved PLM’s sensitivity to forskolin in terms of suppression of INaCa, whereas mutating serine68 to alanine (S68A) abolished PLM’s inhibitory effect on INaCa. Mutating serine68 to glutamic acid (phosphomimetic) resulted in additional suppression of INaCa as compared to wild-type PLM. These results suggest that PLM phosphorylated at serine68 inhibited INaCa. The physiological significance of inhibition of NCX1 by phosphorylated PLM was evaluated in PLM-knockout (KO) mice. When compared to wild-type myocytes, INaCa was significant larger in PLM-KO myocytes. In addition, PMA-induced increase in INaCa was significantly higher in PLM-KO myocytes. By contrast, forskolin had no effect on INaCa in wild-type myocytes. We conclude that PLM, when phosphorylated at serine68, inhibits Na+/Ca2+ exchange in the heart.


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