| In this study we present detailed kinetic models of CaV 1.2 and RyR that interact within a subcellular restricted space. These models are incorporated into the LRd model of the mammalian ventricular cell and validated with an array of experimental data. With the detailed models, we are able to examine CaV 1.2 and RyR channel-state occupancy during the action potential (AP) and gain greater understanding of how CaV 1.2 and RyR channels respond to pacing frequency and how these channels modulate intracellular Ca2+ ([Ca2+]i), the Ca2+ transient (CaT), and membrane potential.; In addition, we use the models to study the mechanism by which lethal arrhythmia, specifically, catecholaminergic polymorphic ventricular tachycardia (CPVT), can be initiated in patients with a missense mutation of the calsequestrin 2 gene (CASQ2). This mutation (CASQ2D307H) results in a decreased ability of CASQ2 to bind free calcium (Ca2+) in the sarcoplasmic reticulum (SR). We investigate the mutation's effect on SR Ca 2+ storage, the Ca2+ transient (CaT) and its indirect effect on ionic currents and membrane potential. Because CPVT is observed on the background of beta-adrenergic stimulation, we incorporate changes to ICa(L) and other currents, reflecting the application of a saturating concentration of ISO and show how the combination of rapid pacing, +ISO, +CASQ2 D307H, and a pause, all of which allow for SR Ca2+ to increase to a threshold level, results in store-overload induced SR Ca 2+ release (SOICR). The bolus of [Ca2+]i released by the SR is removed by the electrogenic Na+-Ca 2+ exchanger, generating a delayed-afterdepolarization (DAD) which can initiate a spontaneous AP, thus providing a mechanistic link between the CASQ mutation and cardiac arrhythmia. |
