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Research ArticleArticle

Biased Effect of Cardiotonic Steroids on Na/K-ATPase–Mediated Signal Transduction

Yunhui Xu, Pauline Marck, Minqi Huang, Jeffrey X. Xie, Tong Wang, Joseph I. Shapiro, Liquan Cai, Feng Feng and Zijian Xie
Molecular Pharmacology March 2021, 99 (3) 217-225; DOI: https://doi.org/10.1124/molpharm.120.000101
Yunhui Xu
Marshall Institute for Interdisciplinary Research, Huntington, West Virginia (Y.X., P.M., M.H., T.W., L.C., Z.X.); University of Toledo College of Medicine and Life Sciences, Toledo, Ohio (J.X.X.); Joan C. Edwards School of Medicine at Marshall University, Huntington, West Virginia (J.I.S.); and Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, P. R. China, and Jiangsu Food and Pharmaceutical Science College, Huai’an, P. R. China (F.F.)
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Pauline Marck
Marshall Institute for Interdisciplinary Research, Huntington, West Virginia (Y.X., P.M., M.H., T.W., L.C., Z.X.); University of Toledo College of Medicine and Life Sciences, Toledo, Ohio (J.X.X.); Joan C. Edwards School of Medicine at Marshall University, Huntington, West Virginia (J.I.S.); and Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, P. R. China, and Jiangsu Food and Pharmaceutical Science College, Huai’an, P. R. China (F.F.)
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Minqi Huang
Marshall Institute for Interdisciplinary Research, Huntington, West Virginia (Y.X., P.M., M.H., T.W., L.C., Z.X.); University of Toledo College of Medicine and Life Sciences, Toledo, Ohio (J.X.X.); Joan C. Edwards School of Medicine at Marshall University, Huntington, West Virginia (J.I.S.); and Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, P. R. China, and Jiangsu Food and Pharmaceutical Science College, Huai’an, P. R. China (F.F.)
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Jeffrey X. Xie
Marshall Institute for Interdisciplinary Research, Huntington, West Virginia (Y.X., P.M., M.H., T.W., L.C., Z.X.); University of Toledo College of Medicine and Life Sciences, Toledo, Ohio (J.X.X.); Joan C. Edwards School of Medicine at Marshall University, Huntington, West Virginia (J.I.S.); and Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, P. R. China, and Jiangsu Food and Pharmaceutical Science College, Huai’an, P. R. China (F.F.)
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Tong Wang
Marshall Institute for Interdisciplinary Research, Huntington, West Virginia (Y.X., P.M., M.H., T.W., L.C., Z.X.); University of Toledo College of Medicine and Life Sciences, Toledo, Ohio (J.X.X.); Joan C. Edwards School of Medicine at Marshall University, Huntington, West Virginia (J.I.S.); and Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, P. R. China, and Jiangsu Food and Pharmaceutical Science College, Huai’an, P. R. China (F.F.)
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Joseph I. Shapiro
Marshall Institute for Interdisciplinary Research, Huntington, West Virginia (Y.X., P.M., M.H., T.W., L.C., Z.X.); University of Toledo College of Medicine and Life Sciences, Toledo, Ohio (J.X.X.); Joan C. Edwards School of Medicine at Marshall University, Huntington, West Virginia (J.I.S.); and Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, P. R. China, and Jiangsu Food and Pharmaceutical Science College, Huai’an, P. R. China (F.F.)
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Liquan Cai
Marshall Institute for Interdisciplinary Research, Huntington, West Virginia (Y.X., P.M., M.H., T.W., L.C., Z.X.); University of Toledo College of Medicine and Life Sciences, Toledo, Ohio (J.X.X.); Joan C. Edwards School of Medicine at Marshall University, Huntington, West Virginia (J.I.S.); and Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, P. R. China, and Jiangsu Food and Pharmaceutical Science College, Huai’an, P. R. China (F.F.)
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Feng Feng
Marshall Institute for Interdisciplinary Research, Huntington, West Virginia (Y.X., P.M., M.H., T.W., L.C., Z.X.); University of Toledo College of Medicine and Life Sciences, Toledo, Ohio (J.X.X.); Joan C. Edwards School of Medicine at Marshall University, Huntington, West Virginia (J.I.S.); and Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, P. R. China, and Jiangsu Food and Pharmaceutical Science College, Huai’an, P. R. China (F.F.)
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Zijian Xie
Marshall Institute for Interdisciplinary Research, Huntington, West Virginia (Y.X., P.M., M.H., T.W., L.C., Z.X.); University of Toledo College of Medicine and Life Sciences, Toledo, Ohio (J.X.X.); Joan C. Edwards School of Medicine at Marshall University, Huntington, West Virginia (J.I.S.); and Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, P. R. China, and Jiangsu Food and Pharmaceutical Science College, Huai’an, P. R. China (F.F.)
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Abstract

Recent studies have revealed that Na/K-ATPase (NKA) can transmit signals through ion-pumping–independent activation of pathways relayed by distinct intracellular protein/lipid kinases, and endocytosis challenges the traditional definition that cardiotonic steroids (CTS) are NKA inhibitors. Although additional effects of CTS have long been suspected, revealing its agonist impact through the NKA receptor could be a novel mechanism in understanding the basic biology of NKA. In this study, we tested whether different structural CTS could trigger different sets of NKA/effector interactions, resulting in biased signaling responses without compromising ion-pumping capacity. Using purified NKA, we found that ouabain, digitoxigenin, and somalin cause comparable levels of NKA inhibition. However, although endogenous ouabain stimulates both protein kinases and NKA endocytosis, digitoxigenin and somalin bias to protein kinases and endocytosis, respectively, in LLC-PK1 cells. The positive inotropic effects of CTS are traditionally regarded as NKA inhibitors. However, CTS-induced signaling occurs at concentrations at least one order of magnitude lower than that of inotropy, which eliminates their well known toxic actions on the heart. The current study adds a novel mechanism that CTS could exert its biased signaling properties through the NKA signal transducer.

SIGNIFICANCE STATEMENT Although it is now well accepted that NKA has an ion-pumping–independent signaling function, it is still debated whether direct and conformation-dependent NKA/effector interaction is a key to this function. Therefore, this investigation is significant in advancing our understanding of the basic biology of NKA-mediated signal transduction and gaining molecular insight into the structural elements that are important for cardiotonic steroid’s biased action.

Footnotes

    • Received June 25, 2020.
    • Accepted December 24, 2020.
  • This work was supported by the American Heart Association (AHA) postdoctoral fellowship [18POST33990237]; National Institutes of Health National Heart, Lung, and Blood Institute [HL109015]; and the Marshall Institute for Interdisciplinary Research (MIIR) fund.

  • The authors declare no competing interests.

  • Zijian Xie is deceased.

  • https://doi.org/10.1124/molpharm.120.000101.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 99 (3)
Molecular Pharmacology
Vol. 99, Issue 3
1 Mar 2021
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Research ArticleArticle

CTS Bias

Yunhui Xu, Pauline Marck, Minqi Huang, Jeffrey X. Xie, Tong Wang, Joseph I. Shapiro, Liquan Cai, Feng Feng and Zijian Xie
Molecular Pharmacology March 1, 2021, 99 (3) 217-225; DOI: https://doi.org/10.1124/molpharm.120.000101

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Research ArticleArticle

CTS Bias

Yunhui Xu, Pauline Marck, Minqi Huang, Jeffrey X. Xie, Tong Wang, Joseph I. Shapiro, Liquan Cai, Feng Feng and Zijian Xie
Molecular Pharmacology March 1, 2021, 99 (3) 217-225; DOI: https://doi.org/10.1124/molpharm.120.000101
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