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.
Gene expression data has been deposited in GEO under accession code GSE48760
Transcriptomes of the hybrid mouse diversity panel subjected to Isoproterenol challengePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE48760).
- Colin M Rees
- Jun-Hai Yang
- Marc Santolini
- Aldons J Lusis
- James N Weiss
- Alain Karma
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: This study was approved by the UCLA Chancellor's Animal Research Committee (ARC 2003-063-23B) and performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the United States National Institutes of Health (NIH Publication No. 85-23, revised 1996) and with UCLA Policy 990 on the Use of Laboratory Animal Subjects in Research (revised 2010).
- José D Faraldo-Gómez, National Heart, Lung and Blood Institute, National Institutes of Health, United States
© 2018, Rees et al.
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.
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