The Ca2+ transient as a feedback sensor controlling cardiomyocyte ionic conductances in mouse populations

• Published in: eLife Vol. 7
• Main Authors: Rees, Colin M, Yang, Jun-Hai, Santolini, Marc, Lusis, Aldons J, Weiss, James N, Karma, Alain
• Format: Journal Article
• Language: English
• Published: Cambridge eLife Sciences Publications Ltd 25.09.2018; eLife Sciences Publications, Ltd
• Subjects: Action potential; Algorithms; Calcium (intracellular); cardiac electrophysiology; cardiac homeostasis; Cardiac muscle; Cardiomyocytes; Computational and Systems Biology; computational biology; Feedback; Gene expression; Heart; Ion channels; Medicine; Myocytes; Physics of Living Systems; Population; Potassium currents; Ventricle; Los Angeles California; United States > US; California
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.36717

Conductances of ion channels and transporters controlling cardiac excitation may vary in a population of subjects with different cardiac gene expression patterns. However, the amount of variability and its origin are not quantitatively known. We propose a new conceptual approach to predict this variability that consists of finding combinations of conductances generating a normal intracellular Ca2+ transient without any constraint on the action potential. Furthermore, we validate experimentally its predictions using the Hybrid Mouse Diversity Panel, a model system of genetically diverse mouse strains that allows us to quantify inter-subject versus intra-subject variability. The method predicts that conductances of inward Ca2+ and outward K+ currents compensate each other to generate a normal Ca2+ transient in good quantitative agreement with current measurements in ventricular myocytes from hearts of different isogenic strains. Our results suggest that a feedback mechanism sensing the aggregate Ca2+ transient of the heart suffices to regulate ionic conductances.