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

Colin M Rees,Jun-Hai Yang,James N Weiss,Marc Santolini,Alain Karma,Aldons J Lusis

doi:10.7554/elife.36717

Abstract

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.

Highlights

Following the landmark publication of the Hodgkin-Huxley model of nerve-cell action potential over six decades ago (Hodgkin and Huxley, 1952), electrophysiological models of increasing complexity have been developed to describe the cardiac action potential (AP) and its interaction with the intracellular calcium (Ca2+) signal (Noble, 2011; Silva and Rudy, 2010), which links electrical signaling to mechanical contraction in cardiomycoytes (Bers, 2001)
Our hypothesis is that the calcium transient (CaT) is critical for generating blood pressure, which is sensed by the carotid baroreceptors and feeds back through the autonomic nervous system to regulate the CaT via controlling levels of Ca-cyling proteins and the AP in a way that preserves blood pressure
This is revealed by a good enough solutions’ (GES) search with only Ca2+ sensing (S1 and S2) that yields a broader histogram for the in addition to the exchanger (INaCa) conductance (Figure 3—figure supplement 1)

Summary

Introduction

Following the landmark publication of the Hodgkin-Huxley model of nerve-cell action potential over six decades ago (Hodgkin and Huxley, 1952), electrophysiological models of increasing complexity have been developed to describe the cardiac action potential (AP) and its interaction with the intracellular calcium (Ca2+) signal (Noble, 2011; Silva and Rudy, 2010), which links electrical signaling to mechanical contraction in cardiomycoytes (Bers, 2001). Ca2+ release and uptake from the SR causes a transient rise in cytosolic Ca2+ concentration, the calcium transient (CaT), which activates myocyte contraction. Those cellular-scale models have been traditionally constructed by piecing together separate mathematical models describing molecular-scale

Methods

Results

Conclusion