Background: Phospholamban (PLN) is an important regulatory protein to inhibit the Serca pump (SERCA2a). Since SERCA2a uptakes the cytosolic calcium ions back to SR, PLN then plays an important role in the intracellular Ca2+ handling. In this paper, we studied one kind of phospholamban mutation “R25C-PLN”and built its mutation model. There are two main effects of this mutation. On one hand, R25C-PLN enhances the inhibitory effect of PLN on SERCA2a, resulting in depressed Ca2+ activities and reduced propensity of arrhythmia. On the other hand, R25C-PLN also enhances the activities of RyR2, leading to more frequent Ca2+ events, such as calcium spark and calcium wave and so seems to be proarrhythmia.
Methods: Simulations of the cardiac channelopathies were based on a modified ORd model of the human ventricular cardiomyocyte with phospholamban mutation effects, in which the mutative Ca2+ handling and signaling cascade from ISO application to PKA phosphorylation of target proteins were incorporated.
Results: We built up related mathematical models to explore these phenomena and underlying arrhythmia mechanisms. We have successfully simulated the arrhythmia phenomena related to R25C-PLN mutation. Furthermore, when we ablated PLN mutation, some phenomena were reversed: enhanced uptake of Serca pump, increased SR Ca2+ level, and increased cytosolic Ca2+ transient.
Conclusion: These phenomena suggest the underlying arrhythmia mechanism: depressed uptake of Serca pump leads to increased cytosolic Ca2+ concentration, eliciting depolarization current of NCX, resulting in DAD-triggered arrhythmia.