An Integrative Model of the Cardiac Ventricular Myocyte Incorporating Local Control of Ca 2+ Release

Abstract

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.