A model for cooperative gating of L-type Ca2+ channels and its effects on cardiac alternans dynamics

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.Author summary: Recent experimental studies have suggested that clusters of L-type CaV1.2 channels (LTCCs) can open and close in unison (i.e., cooperative or coupled gating) and that this gating modality may regulate excitation-contraction coupling in the heart. However, whether amplification of Ca2+ influx by cooperative gating of LTCCs promotes alternans is unknown. In this study, we developed a novel computational model of cooperative gating of LTCCs from experimental data. We incorporate the model into a physiologically detailed action potential (AP) model and investigated how changes in coupling strength of LTCCs may impact dynamics of AP and Ca2+ alternans. Our data suggest that increasing coupling strength of LTCCs prolongs AP duration and leads to Ca2+ overload. In addition, our theoretical and computational approaches elucidate that increasing coupling strength of LTCCs promotes positive Cai→Vm coupling, which could lead to Vm-driven and Ca2+-driven alternans.