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Molecular Pharmacology

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Research ArticleArticle

Activation of (Na++K+)-ATPase Modulates Cardiac L-Type Ca2+ Channel Function

Dong I. Lee, Michael G. Klein, Weizhong Zhu, Rui-Ping Xiao, Volodymyr Gerzanich and Kai Y. Xu
Molecular Pharmacology April 2009, 75 (4) 774-781; DOI: https://doi.org/10.1124/mol.108.052597
Dong I. Lee
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Michael G. Klein
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Weizhong Zhu
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Rui-Ping Xiao
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Volodymyr Gerzanich
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Kai Y. Xu
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Abstract

Cellular Ca2+ signaling underlies diverse vital biological processes, including muscle contractility, memory encoding, fertilization, cell survival, and cell death. Despite extensive studies, the fundamental control mechanisms that regulate intracellular Ca2+ movement remain enigmatic. We have found recently that activation of the (Na++K+)-ATPase markedly potentiates intracellular Ca2+ transients and contractility of rat heart cells. Little is known about the pathway responsible for the activation of the (Na++K+)-ATPase-initiated Ca2+ signaling. Here, we demonstrate a novel mechanism in which activation of the (Na++K+)-ATPase is coupled to increased L-type Ca2+ channel function through a signaling cascade involving Src and ERK1/2 but not well established regulators of the channel, such as adrenergic receptor system or activation of PKA or CaMKII. We have also identified Ser1928, a phosphorylation site for the α1 subunit of the L-type Ca2+ channel that may participate in the activation of the (Na++K+)-ATPase-mediated Ca2+ signaling. The findings reported here uncover a novel molecular cross-talk between activation of the (Na++K+)-ATPase and L-type Ca2+ channel and provide new insights into Ca2+ signaling mechanisms for deeper understanding of the nature of cellular Ca2+ handling in heart.

Footnotes

  • This work was supported in part by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL52175]; by the National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases [Grant AR44197]; by the Intramural Research program of the National Institutes of Health National Institute on Aging; and by a seed grant from Johnson & Johnson.

  • D.I.L. and M.G.K. contributed equally to this work.

  • ABBREVIATIONS: NKA, (Na++K+)-ATPase or sodium and potassium ion activated adenosinetriphosphatase (EC 3.6.1.3); NCX, Na+/Ca2+ exchanger; PP1, 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine; N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline; LTCC, L-type Ca2+ channels; BAPTA, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid; PD98059, 2′-amino-3′-methoxyflavone; AR, adrenergic receptor; PKA, protein kinase A; CaM, Ca2+/calmodulin; CaMKII, Ca2+/calmodulin-dependent protein kinase II; CICR, Ca2+ induced Ca2+ release mechanism; PKC, protein kinase C; SSA412, site-specific antibody 412.

    • Received October 8, 2008.
    • Accepted January 2, 2009.
  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 75 (4)
Molecular Pharmacology
Vol. 75, Issue 4
1 Apr 2009
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Research ArticleArticle

Activation of (Na++K+)-ATPase Modulates Cardiac L-Type Ca2+ Channel Function

Dong I. Lee, Michael G. Klein, Weizhong Zhu, Rui-Ping Xiao, Volodymyr Gerzanich and Kai Y. Xu
Molecular Pharmacology April 1, 2009, 75 (4) 774-781; DOI: https://doi.org/10.1124/mol.108.052597

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Research ArticleArticle

Activation of (Na++K+)-ATPase Modulates Cardiac L-Type Ca2+ Channel Function

Dong I. Lee, Michael G. Klein, Weizhong Zhu, Rui-Ping Xiao, Volodymyr Gerzanich and Kai Y. Xu
Molecular Pharmacology April 1, 2009, 75 (4) 774-781; DOI: https://doi.org/10.1124/mol.108.052597
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