Transitions Among Excitable, Oscillatory and Non-Excitable in Simplified Calcium Cycling Model

Abstract

Calcium (Ca) plays a central role in cardiac excitation-contraction coupling. Under normal conditions, Ca entering through the L-type Ca channel opens ryanodine receptors (RyRs), which are regulated by cytosolic ([Ca]i) and luminal Ca ([Ca]SR), and causes Ca release from the sarcoplasmic reticulum (SR). This positive feedback by Ca induced Ca release makes the Ca cycling excitable. However, as the cell goes to pathological conditions, Ca releases from the SR occurs spontaneously, leading to Ca oscillation. This transition from excitable to oscillatory can be caused by different factors, including Ca overload, RyR sensitization, SERCA uptake regulation, and structural remodeling etc. Here we use a simplified model of intracellular Ca cycling to investigate how each factor contributes to Ca cycling dynamics and shifts the system among excitable, oscillatory and non-excitable states. We find that: Increase of RyR sensitivity decreases the [Ca]SR threshold for Ca oscillation. When [Ca]SR is far from the threshold, increasing RyR sensitivity only is not enough to induce oscillation. As the system approaches [Ca]SR threshold, increasing RyR sensitivity only can induce oscillation by changing the system from excitable to oscillatory. In the oscillatory regime, increasing RyR sensitivity leads to more frequent oscillation at low [Ca]SR; However, if the RyR sensitivity becomes too low or too high, Ca oscillation is abolished. 2) Below the threshold, increase in extracellular [Ca] ([Ca]o) leads to increase in [Ca]SR and release amplitude; Above the [Ca]SR threshold, increase in [Ca]o leads to increase in oscillation frequency, decreases in oscillation amplitude and basal [Ca]SR. 3) Increase of SERCA pump increases the threshold for Ca oscillation; If SERCA is too low it cannot support Ca oscillation.