Computational Evidence of Centripetal Propagating “Ca2+-Induced-Ca2+-Release” in Stimulated Cardiac Purkinje Cells

Abstract

sarcolemma or nuclear membranes), cytosolic (minimal distance to membranes >5mm) or nuclear. Nuclear events were considered membrane associated when occurring at a distance <1mm from the nuclear envelope or membranes of the nucleoplasmic reticulum. With tetracaine the Ca spark frequency decreased to 0.750.3 (from 8.851.2 in control), whereas the frequency of events detected after subsequent addition of IP3 increased to 2.951.3 (events/100mm/s). Subsequent exposure to 2-APB reduced the frequency to 1.850.8. Compared to Ca sparks, local Ca release events in the presence of IP3 were lower in amplitude, prolonged in duration and had a slower rise time. The increase in frequency of local Ca release events was particularly pronounced in the perinucler regions compared to the cytosol or the subsarcolemmal space. Furthermore, IP3-mediated Ca release events could also be detected within the nucleus. These nuclear events occurred at a higher incidence at locations that were closely associated with membrane structures of the nuclear envelope or the nucleoplasmic reticulum. In conclusion, in atrial myocytes IP3Rmediated Ca release is spatially inhomogeneous and preferentially occurs in the nuclear and perinuclear regions. Background: In cardiac cells, sarcoplasmic reticulum (SR) Ca 2þ -channels (RyRs) are regrouped into clusters, so-called Ca 2þ -release units (CRUs). Dynamic regulation of the individual RyRs in the cluster determines the characteristics of the SR-Ca 2þ -efflux during cell activation. The Ca 2þ -sensitivity of the channel plays a central role in this regulation. However, technical limitations make it difficult to directly assess the mechanism underlying the Ca 2þ -sensitivity of SR-Ca 2þ -release in the micro-domain of a CRU. Thus, mathematical models simulating intracellular Ca 2þ activities, such as Ca 2þ sparks and waves, incorporate a Ca 2þ -release function which approximates or, frequently, omits the regulation in the cluster micro-domain. Moreover, using nano-scale components (such as realistic spacing between RyRs in a CRU) in a micro-scale computational domain intending to reproduce the cell geometry requires massive computational resources. Method: To overcome both experimental and computational limitations, we developed a time-dependent Ca 2þ -release function that addresses activation and termination of Ca 2þ -release, mediated by dynamic regulatory mechanisms. This function has been used in systems of ODEs and PDEs applied to cardiac Purkinje cells (Pcells), which included other intracellular modulators of Ca 2þ transients, such as Ca 2þ -buffers and Ca 2þ -pumps. Results : Compared to experimental data from Pcells, the Ca 2þ -release function could predict the instantaneous variation of Ca 2þ -efflux from the CRU. Predicted values for the activation threshold of [Ca 2þ ] at the cytosolic side for RyR2 and RyR3 in Pcells were found to be 160 nM-190 nM and 105 nM-110 nM, respectively. These results matched the experimental findings. Conclusion: This function has been used successfully in 1D and 2...