Abstract
The local control theory of excitation-contraction (EC) coupling asserts that regulation of calcium (Ca2+) release occurs at the nanodomain level, where openings of single L-type Ca2+ channels (LCCs) trigger openings of small clusters of ryanodine receptors (RyRs) co-localized within the dyad. A consequence of local control is that the whole-cell Ca2+ transient is a smooth continuous function of influx of Ca2+ through LCCs. While this so-called graded release property has been known for some time, its functional importance to the integrated behavior of the cardiac ventricular myocyte has not been fully appreciated. We previously formulated a biophysically based model, in which LCCs and RyRs interact via a coarse-grained representation of the dyadic space. The model captures key features of local control using a low-dimensional system of ordinary differential equations. Voltage-dependent gain and graded Ca2+ release are emergent properties of this model by virtue of the fact that model formulation is closely based on the sub-cellular basis of local control. In this current work, we have incorporated this graded release model into a prior model of guinea pig ventricular myocyte electrophysiology, metabolism, and isometric force production. The resulting integrative model predicts the experimentally observed causal relationship between action potential (AP) shape and timing of Ca2+ and force transients, a relationship that is not explained by models lacking the graded release property. Model results suggest that even relatively subtle changes in AP morphology that may result, for example, from remodeling of membrane transporter expression in disease or spatial variation in cell properties, may have major impact on the temporal waveform of Ca2+ transients, thus influencing tissue level electromechanical function.
Highlights
Since publication of the first computational model of the cardiac myocyte action potential (AP) in 1960 (Noble, 1960), the range of biological processes described in models of the cardiac myocyte has grown continuously
Ca2+-induced Ca2+-release (CICR) DURING THE ACTION POTENTIAL Figure 5A shows the model AP, which has a steady-state duration of 189 ms at 1 Hz pacing
A delay of 144–190 ms is supported by experimental recordings (Sipido et al, 1995b; Grantham and Cannell, 1996; see Figures 5B,E) and by the prediction of local control theory that local fidelity of excitation-contraction coupling (ECC) decreases at highly depolarized potentials, such as those that occur early in the guinea pig AP
Summary
Since publication of the first computational model of the cardiac myocyte action potential (AP) in 1960 (Noble, 1960), the range of biological processes described in models of the cardiac myocyte has grown continuously. While the integrative nature of today’s most commonly used models differ, the sub-cellular processes for which there are quantitative, experimentally based models include: (a) voltage-gated ion channels and currents; (b) intracellular calcium (Ca2+) dynamics and Ca2+-induced Ca2+-release (CICR); (c) electrogenic and ATP-dependent membrane transporters; (d) regulation of intracellular Ca2+, sodium (Na+), potassium (K+), and hydrogen ion (H+) concentrations; (e) mitochondrial ATP production and its regulation; (f) coupling of ATP production to energy requiring membrane transporters and myofilaments; and (g) ligand gated membrane receptors and intracellular signaling pathways. The close interplay between modeling and experiments has enabled a remarkably deep understanding of the function of cardiac myocytes. Models play a central role in understanding the relationships between molecular function and the integrated behavior of the cardiac myocyte in health and disease
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
