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J. Biol. Chem., Vol. 279, Issue 24, 25211-25218, June 11, 2004

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ERK1/2 Mediates Insulin Stimulation of Na,K-ATPase by Phosphorylation of the -Subunit in Human Skeletal Muscle Cells^*

Lubna Al-Khalili, Olga Kotova, Hiroki Tsuchida, Ingrid Ehrén¶, Eric Féraille||, Anna Krook**, and Alexander V. Chibalin

From the Section of Integrative Physiology, Department of Surgical Sciences, the ^¶Section of Urology, Department of Surgical Sciences, and the ^**Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden and the ^||Division de Néphrologie, Hôpital Cantonal Universitaire, Genève CH-1211, Switzerland

Insulin stimulates Na⁺,K⁺-ATPase activity and induces translocation of Na⁺,K⁺-ATPase molecules to the plasma membrane in skeletal muscle. We determined the molecular mechanism by which insulin regulates Na⁺,K⁺-ATPase in differentiated primary human skeletal muscle cells (HSMCs). Insulin action on Na⁺,K⁺-ATPase was dependent on ERK1/2 in HSMCs. Sequence analysis of Na⁺,K⁺-ATPase -subunits revealed several potential ERK phosphorylation sites. Insulin increased ouabain-sensitive ⁸⁶Rb⁺ uptake and [³H]ouabain binding in intact cells. Insulin also increased phosphorylation and plasma membrane content of the Na⁺,K⁺-ATPase ₁- and ₂-subunits. Insulin-stimulated Na⁺,K⁺-ATPase activation, phosphorylation, and translocation of -subunits to the plasma membrane were abolished by 20 µM PD98059, which is an inhibitor of MEK1/2, an upstream kinase of ERK1/2. Furthermore, inhibitors of phosphatidylinositol 3-kinase (100 nM wortmannin) and protein kinase C (10 µM GF109203X) had similar effects. Notably, insulin-stimulated ERK1/2 phosphorylation was abolished by wortmannin and GF109203X in HSMCs. Insulin also stimulated phosphorylation of ₁- and ₂-subunits on Thr-Pro amino acid motifs, which form specific ERK substrates. Furthermore, recombinant ERK1 and -2 kinases were able to phosphorylate -subunit of purified human Na⁺,K⁺-ATPase in vitro. In conclusion, insulin stimulates Na⁺,K⁺-ATPase activity and translocation to plasma membrane in HSMCs via phosphorylation of the -subunits by ERK1/2 mitogen-activated protein kinase.

Received for publication, February 26, 2004 , and in revised form, April 2, 2004.

^* This work was supported by grants from the Swedish Research Council, the Swedish Heart and Lung Foundation, the Novo-Nordisk Foundation, and the Swedish Society of Medicine and Creative Peptides Sweden AB. 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.

Both authors have contributed equally to this work.

To whom correspondence should be addressed: Dept. of Surgical Sciences, Section of Integrative Physiology, Karolinska Institutet, von Eulers väg 4, 4 tr, SE-171 77 Stockholm, Sweden. Tel.: 46-8-524-87584; Fax: 46-8-335-436; E-mail: Alexander.Chibalin{at}kirurgi.ki.se.

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