A model for cooperative gating of L-type Ca ²⁺ channels and its effects on cardiac alternans dynamics

Abstract

In ventricular myocytes, membrane depolarization during the action potential (AP) causes synchronous activation of multiple L-type Ca _V1.2 channels (LTCCs), which trigger the release of calcium (Ca ²⁺) from the sarcoplasmic reticulum (SR). This results in an increase in intracellular Ca ²⁺ (Ca _i) 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 (V _m) due to steep AP duration (APD) restitution (V _m-driven alternans), instability of Ca _i cycling (Ca ²⁺-driven alternans), or both, and may be modulated by functional coupling between clustered Ca _V1.2 (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 Ca ²⁺ dynamics in the heart. We found that increasing the degree of coupling between LTCCs increases the amplitude of Ca ²⁺ currents (I _CaL) 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 Ca ²⁺ on the membrane voltage (Ca _i→V _m coupling) more positive and destabilizes the V _m-Ca _i dynamics for V _m-driven alternans and Ca _i-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 Ca _i→V _m coupling and potentially promoting cardiac arrhythmias.

Author summary

Recent experimental studies have suggested that clusters of L-type Ca _V1.2 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 Ca ²⁺ 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 Ca ²⁺ alternans. Our data suggest that increasing coupling strength of LTCCs prolongs AP duration and leads to Ca ²⁺ overload. In addition, our theoretical and computational approaches elucidate that increasing coupling strength of LTCCs promotes positive Ca _i→V _m coupling, which could lead to V _m-driven and Ca ²⁺-driven alternans.