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J. Biol. Chem., Vol. 283, Issue 1, 476-486, January 4, 2008

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Phosphorylation of Phospholemman (FXYD1) by Protein Kinases A and C Modulates Distinct Na,K-ATPase Isozymes^*

From the Department of Pharmacology and Toxicology, University of Lausanne, 27 Rue du Bugnon, 1005 Lausanne, Switzerland

Phospholemman (FXYD1), mainly expressed in heart and skeletal muscle, is a member of the FXYD protein family, which has been shown to decrease the apparent K⁺ and Na⁺ affinity of Na,K-ATPase ( Crambert, G., Fuzesi, M., Garty, H., Karlish, S., and Geering, K. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 11476-11481[Abstract/Free Full Text] ). In this study, we use the Xenopus oocyte expression system to study the role of phospholemman phosphorylation by protein kinases A and C in the modulation of different Na,K-ATPase isozymes present in the heart. Phosphorylation of phospholemman by protein kinase A has no effect on the maximal transport activity or on the apparent K⁺ affinity of Na,K-ATPase 1/β1 and 2/β1 isozymes but increases their apparent Na⁺ affinity, dependent on phospholemman phosphorylation at Ser⁶⁸. Phosphorylation of phospholemman by protein kinase C affects neither the maximal transport activity of 1/β1 isozymes nor the K⁺ affinity of 1/β1 and 2/β1 isozymes. However, protein kinase C phosphorylation of phospholemman increases the maximal Na,K-pump current of 2/β1 isozymes by an increase in their turnover number. Thus, our results indicate that protein kinase A phosphorylation of phospholemman has similar functional effects on Na,K-ATPase 1/β and 2/β isozymes and increases their apparent Na⁺ affinity, whereas protein kinase C phosphorylation of phospholemman modulates the transport activity of Na,K-ATPase 2/β but not of 1/β isozymes. The complex and distinct regulation of Na,K-ATPase isozymes by phosphorylation of phospholemman may be important for the efficient control of heart contractility and excitability.

Received for publication, July 16, 2007 , and in revised form, November 6, 2007.

^* This work was supported by Swiss National Science Foundation Grant 3100A0-107513 (to K. G.). 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. Tel.: 41-21-692-54-10; Fax: 41-21-692-53-55; E-mail: Kaethi.Geering{at}unil.ch.

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