Profound regulation of Na/K pump activity by transient elevations of cytoplasmic calcium in murine cardiac myocytes

Abstract
Article and author information
Metrics

Abstract

Small changes of Na/K pump activity regulate internal Ca release in cardiac myocytes via Na/Ca exchange. We now show conversely that transient elevations of cytoplasmic Ca strongly regulate cardiac Na/K pumps. When cytoplasmic Na is submaximal, Na/K pump currents decay rapidly during extracellular K application and multiple results suggest that an inactivation mechanism is involved. Brief activation of Ca influx by reverse Na/Ca exchange enhances pump currents and attenuates current decay, while repeated Ca elevations suppress pump currents. Pump current enhancement reverses over 3 min, and results are similar in myocytes lacking the regulatory protein, phospholemman. Classical signaling mechanisms, including Ca-activated protein kinases and reactive oxygen, are evidently not involved. Electrogenic signals mediated by intramembrane movement of hydrophobic ions, such as hexyltriphenylphosphonium (C6TPP), increase and decrease in parallel with pump currents. Thus, transient Ca elevation and Na/K pump inactivation cause opposing sarcolemma changes that may affect diverse membrane processes.

Article and author information

Author details

Fang-Min Lu

Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Christine Deisl

Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Donald W Hilgemann

Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, United States

For correspondence
donald.hilgemann@utsouthwestern.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5288-5133

Funding

NIH Office of the Director (RO1 #1129843)

Donald W Hilgemann

Endowed Professor Collaborative Research Support, Charles and Jane Pak Center of Mineral Metabolism and Clinical Research (Collaborative Research Support)

Donald W Hilgemann

American Heart Association (Fellowship #30950013)

Christine Deisl

The funder (NIH) had no role in study design, data collection, interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols. The protocol was approved by the Committee on the Ethics of Animal Experiments of the University of Texas Southwestern Medical center at Dallas (Protocol Number: 2015-101114). Euthanasia was performed with flurane and every effort was made to minimize suffering.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.