Local Control Model Illustrates How Action Potential Morphology Affects Ca2+ Release

Abstract

The local control theory of excitation-contraction (EC) coupling states 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. This control scheme leads to the EC coupling properties of voltage-dependent gain and graded release. We have formulated a deterministic “coupled LCC-RyR model” that captures these properties. The model presented here combines our local control model with a prior model of guinea pig ventricular myocyte electrophysiology, metabolism, and isometric force production. It reconstructs many features of Ca2+-induced Ca2+-release, but the strongest prediction concerns the relationship between action potential (AP) shape and Ca2+ release timing. In species expressing the transient outward current (Ito), APs exhibit a “notch” and Ca2+ transients peak soon after the AP upstroke. However guinea pig lacks Ito, and its Ca2+ transients have been shown to peak much later, aligned with the middle of the plateau phase of the AP. Here the late peak of the Ca2+ transient arises from low initial EC coupling gain at the peak of the AP near +50mV. Gain increases as the AP repolarizes during the plateau. Addition of Ito and thus the AP notch leads to increased gain early in the AP, resulting in Ca2+ transients that peak much earlier. The Ca2+ transient time course controls that of contraction. In larger mammalian hearts, expression levels of Ito vary with transmural depth. Our model predicts these expression differences will have a major impact on the temporal waveform of Ca2+ transients, and therefore timing of contraction. To achieve the most complete understanding of contraction at the whole-heart level, our results indicate that simulations should incorporate both local control and regional expression variability.