In Silico Investigation of the CACNA1C N2091S Mutation in Timothy Syndrome

Abstract

Experimental studies demonstrated that early afterdepolarization (EAD)-mediated triggered activity. And the different EAD inducibility among the three cell types can amplify the electrical difference and thereby dispersion of repolarization, increasing susceptibility to ventricular arrhythmias. Thus, the N2091S mutation confers not only a trigger, but also a substrate for lethal ventricular arrhythmias.

N2091S Mutation in L-type Calcium Channel Promotes Action Potential Alternans in M Cells of Human Ventricle: A Simulation Study

“…In this study, the effect of N2091S mutation on ventricular myocyte electrophysiology and the underlying mechanism of N2091S mutation leading to arrhythmias in M cells were investigated using TP06 model [8] with CaMKII regulation added by Bai [7] at cellular level. The novelty of this paper is to clarify the contribution of N2091S mutation on AP alternans.…”

“…The ten Tusscher et al human ventricular myocyte model (TP06 model) [8] incorporating CaMKII regulation, updated by Bai, was used in this study. Based on the experimental data [6] and N2091S mutant ventricular myocyte model developed by Bai [7], LTCC was altered under the N2091S mutation condition, including steadystate activation d∞, steady-state voltage inactivation f∞ and maximal ICaL conductance GCaL (see in Figure 1A). Eq.…”

“…These parameters related to d∞, f∞ used in the case of the wild type (WT) and N2091S mutation in the model were shown in Table 1. The corresponding values of GCaL in the WT and N2091S mutation type with the reference to Bai' s model [7] were also listed in Table 1. Figure 1B and Figure 1C showed the simulated steady-state activation and inactivation curves under the WT and N2091S mutation conditions, which were consistent with biological experiment results [6].…”

“…Sutphin et al [6] identified CACNA1C-N2091S mutation which was localized in the C-terminus of L-type calcium channel (LTCC) and confirmed that N2091S mutation caused an increased risk for SCD. Bai [7] also found that triggered activity occurred under the N2091S mutation condition at high heart rate. However, the contribution of N2091S mutation on AP alternans is unidentified.…”

“…The simulation results indicated AP alternans was induced only by increasing GCaL rather than LTCC gate parameters d∞ and f∞ in M cells as shown in Figure 3A. GCaL in the WT was set to 0.00003980 mm 3 /(ms•μF), while GCaL in the N2091S mutant was set to 0.00006885 mm 3 /(ms•μF) [7], 172.99% larger than it in the WT. APD gradually increased with the increase of GCaL (Figure 3B) and AP alternans occurred when GCaL exceeded a critical value (156.98% larger than it in the WT).…”