The local control theory of excitation-contraction (EC) coupling in cardiac muscle asserts that L-type Ca(2+) current tightly controls Ca(2+) release from the sarcoplasmic reticulum (SR) via local interaction of closely apposed L-type Ca(2+) channels (LCCs) and ryanodine receptors (RyRs). These local interactions give rise to smoothly graded Ca(2+)-induced Ca(2+) release (CICR), which exhibits high gain. In this study we present a biophysically detailed model of the normal canine ventricular myocyte that conforms to local control theory. The model formulation incorporates details of microscopic EC coupling properties in the form of Ca(2+) release units (CaRUs) in which individual sarcolemmal LCCs interact in a stochastic manner with nearby RyRs in localized regions where junctional SR membrane and transverse-tubular membrane are in close proximity. The CaRUs are embedded within and interact with the global systems of the myocyte describing ionic and membrane pump/exchanger currents, SR Ca(2+) uptake, and time-varying cytosolic ion concentrations to form a model of the cardiac action potential (AP). The model can reproduce both the detailed properties of EC coupling, such as variable gain and graded SR Ca(2+) release, and whole-cell phenomena, such as modulation of AP duration by SR Ca(2+) release. Simulations indicate that the local control paradigm predicts stable APs when the L-type Ca(2+) current is adjusted in accord with the balance between voltage- and Ca(2+)-dependent inactivation processes as measured experimentally, a scenario where common pool models become unstable. The local control myocyte model provides a means for studying the interrelationship between microscopic and macroscopic behaviors in a manner that would not be possible in experiments.

It is now well established that characteristic properties of excitation-contraction (EC) coupling in cardiac myocytes, such as high gain and graded Ca 21 release, arise from the interactions that occur between L-type Ca 21 channels (LCCs) and nearby ryanodine-sensitive Ca 21 release channels (RyRs) in localized microdomains. Descriptions of Ca 21-induced Ca 21 release (CICR) that account for these local mechanisms are lacking from many previous models of the cardiac action potential, and those that do include local control of CICR are able to reconstruct properties of EC coupling, but require computationally demanding stochastic simulations of ;10 5 individual ion channels. In this study, we generalize a recently developed analytical approach for deriving simplified mechanistic models of CICR to formulate an integrative model of the canine cardiac myocyte which is computationally efficient. The resulting model faithfully reproduces experimentally measured properties of EC coupling and whole cell phenomena. The model is used to study the role of local redundancy in L-type Ca 21 channel gating and the role of dyad configuration on EC coupling. Simulations suggest that the characteristic steep rise in EC coupling gain observed at hyperpolarized potentials is a result of increased functional coupling between LCCs and RyRs. We also demonstrate mechanisms by which alterations in the early repolarization phase of the action potential, resulting from reduction of the transient outward potassium current, alters properties of EC coupling.

Stable calcium-induced calcium release (CICR) is critical for maintaining normal cellular contraction during cardiac excitation-contraction coupling. The fundamental element of CICR in the heart is the calcium (Ca(2+)) spark, which arises from a cluster of ryanodine receptors (RyR). Opening of these RyR clusters is triggered to produce a local, regenerative release of Ca(2+) from the sarcoplasmic reticulum (SR). The Ca(2+) leak out of the SR is an important process for cellular Ca(2+) management, and it is critically influenced by spark fidelity, i.e., the probability that a spontaneous RyR opening triggers a Ca(2+) spark. Here, we present a detailed, three-dimensional model of a cardiac Ca(2+) release unit that incorporates diffusion, intracellular buffering systems, and stochastically gated ion channels. The model exhibits realistic Ca(2+) sparks and robust Ca(2+) spark termination across a wide range of geometries and conditions. Furthermore, the model captures the details of Ca(2+) spark and nonspark-based SR Ca(2+) leak, and it produces normal excitation-contraction coupling gain. We show that SR luminal Ca(2+)-dependent regulation of the RyR is not critical for spark termination, but it can explain the exponential rise in the SR Ca(2+) leak-load relationship demonstrated in previous experimental work. Perturbations to subspace dimensions, which have been observed in experimental models of disease, strongly alter Ca(2+) spark dynamics. In addition, we find that the structure of RyR clusters also influences Ca(2+) release properties due to variations in inter-RyR coupling via local subspace Ca(2+) concentration ([Ca(2+)]ss). These results are illustrated for RyR clusters based on super-resolution stimulated emission depletion microscopy. Finally, we present a believed-novel approach by which the spark fidelity of a RyR cluster can be predicted from structural information of the cluster using the maximum eigenvalue of its adjacency matrix. These results provide critical insights into CICR dynamics in heart, under normal and pathological conditions.

Calcium (Ca2+)-induced Ca2+ release (CICR) in cardiac myocytes exhibits high gain and is graded. These properties result from local control of Ca2+ release. Existing local control models of Ca2+ release in which interactions between L-Type Ca2+ channels (LCCs) and ryanodine-sensitive Ca2+ release channels (RyRs) are simulated stochastically are able to reconstruct these properties, but only at high computational cost. Here we present a general analytical approach for deriving simplified models of local control of CICR, consisting of low-dimensional systems of coupled ordinary differential equations, from these more complex local control models in which LCC-RyR interactions are simulated stochastically. The resulting model, referred to as the coupled LCC-RyR gating model, successfully reproduces a range of experimental data, including L-Type Ca2+ current in response to voltage-clamp stimuli, inactivation of LCC current with and without Ca2+ release from the sarcoplasmic reticulum, voltage-dependence of excitation-contraction coupling gain, graded release, and the force-frequency relationship. The model does so with low computational cost.