Abstract
In ventricular myocytes, membrane depolarization during the action potential (AP) causes synchronous activation of multiple L-type CaV1.2 channels (LTCCs), which trigger the release of calcium (Ca2+) from the sarcoplasmic reticulum (SR). This results in an increase in intracellular Ca2+ (Cai) that initiates contraction. During pulsus alternans, cardiac contraction is unstable, going from weak to strong in successive beats despite a constant heart rate. These cardiac alternans can be caused by the instability of membrane potential (Vm) due to steep AP duration (APD) restitution (Vm-driven alternans), instability of Cai cycling (Ca2+-driven alternans), or both, and may be modulated by functional coupling between clustered CaV1.2 (e.g. cooperative gating). Here, mathematical analysis and computational models were used to determine how changes in the strength of cooperative gating between LTCCs may impact membrane voltage and intracellular Ca2+ dynamics in the heart. We found that increasing the degree of coupling between LTCCs increases the amplitude of Ca2+ currents (ICaL) and prolongs AP duration (APD). Increased AP duration is known to promote cardiac alternans, a potentially arrhythmogenic substrate. In addition, our analysis shows that increasing the strength of cooperative activation of LTCCs makes the coupling of Ca2+ on the membrane voltage (Cai→Vm coupling) more positive and destabilizes the Vm-Cai dynamics for Vm-driven alternans and Cai-driven alternans, but not for quasiperiodic oscillation. These results suggest that cooperative gating of LTCCs may have a major impact on cardiac excitation-contraction coupling, not only by prolonging APD, but also by altering Cai→Vm coupling and potentially promoting cardiac arrhythmias.
Highlights
L-type CaV1.2 channels (LTCC) play a critical role in triggering cardiac muscle contraction during the action potential (i.e., excitation-contraction (EC) coupling) [1]
Recent experimental studies have suggested that clusters of L-type CaV1.2 channels (LTCCs) can open and close in unison and that this gating modality may regulate excitation-contraction coupling in the heart
We built a stochastic model of cooperative gating of LTCCs and incorporated this gating modality into the subcellular Ca2+ cycling model, which has realistic Ca2+ compartments and diffusion
Summary
L-type CaV1.2 channels (LTCC) play a critical role in triggering cardiac muscle contraction during the action potential (i.e., excitation-contraction (EC) coupling) [1]. At the membrane potential reached during the plateau phase of the ventricular action potential (AP), LTCCs open, allowing Ca2+ ions to enter the cell. This Ca2+ signal is amplified via Ca2+-induced Ca2+ release through opening of ryanodine receptors (RyRs) from the sarcoplasmic reticulum (SR), which causes a cell-wide increase in Ca2+ that triggers cell contraction [6, 7]. Functional coupling between LTCCs requires Ca2+ for the induction of physical interactions between adjacent channels that leads to amplification of Ca2+ influx. This suggests the intriguing hypothesis that cooperative gating of LTCCs may impact membrane voltage (Vm) and intracellular Ca2+ (Cai) cycling dynamics
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