Ouabain Interaction with Cardiac Na+/K+-ATPase Initiates Signal Cascades Independent of Changes in Intracellular Na+ and Ca2+

Authors

Jiang Liu, Marshall UniversityFollow
Jiang Tian
Michael Haas
Joseph I. Shapiro
Amir Askari
Zijian Xie

Document Type

Article

Publication Date

Fall 9-1-2000

Abstract

We have shown previously that partial inhibition of the cardiac myocyte Na⁺/K⁺-ATPase activates signal pathways that regulate myocyte growth and growth-related genes and that increases in intracellular Ca²⁺ concentration ([Ca²⁺]i) and reactive oxygen species (ROS) are two essential second messengers within these pathways. The aim of this work was to explore the relation between [Ca²⁺]i and ROS. When myocytes were in a Ca²⁺-free medium, ouabain caused no change in [Ca²⁺]i, but it increased ROS as it did when the cells were in a Ca²⁺-containing medium. Ouabain-induced increase in ROS also occurred under conditions where there was little or no change in [Na⁺]i. Exposure of myocytes in Ca²⁺-free medium to monensin did not increase ROS. Increase in protein tyrosine phosphorylation, an early event induced by ouabain, was also independent of changes in [Ca²⁺]i and [Na⁺]i. Ouabain-induced generation of ROS in myocytes was antagonized by genistein, a dominant negative Ras, and myxothiazol/diphenyleneiodonium, indicating a mitochondrial origin for the Ras-dependent ROS generation. These findings, along with our previous data, indicate that increases in [Ca²⁺]i and ROS in cardiac myocytes are induced by two parallel pathways initiated at the plasma membrane: One being the ouabain-altered transient interactions of a fraction of the Na⁺/K⁺-ATPase with neighboring proteins (Src, growth factor receptors, adaptor proteins, and Ras) leading to ROS generation, and the other, inhibition of the transport function of another fraction of the Na⁺/K⁺-ATPase leading to rise in [Ca²⁺]i. Evidently, the gene regulatory effects of ouabain in cardiac myocytes require the downstream collaborations of ROS and [Ca²⁺]i.

Comments

The version of record is available from the publisher at http://www.jbc.org/content/275/36/27838.full.pdf. Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc. All rights reserved. DOI 10.1074/jbc.M002950200

Recommended Citation

Liu, J., Tian, J., Haas, M., Shapiro, J. I., Askari, A., & Xie, Z. (2000). Ouabain interaction with cardiac Na+/K+-ATPase initiates signal cascades independent of changes in intracellular Na+ and Ca2+ concentrations. Journal of Biological Chemistry, 275(36), 27838-27844.