course of a relative PLM phosphorylation level is shown by a solid line. An increase in the phosphorylation level of PLM decreases the Na+ half-saturation constant for the current and effectively increases the pumping rate of Na+ outside the cell. Both PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19636622 time dependences demonstrate similar behavior. Adrenergic Signaling in Mouse Myocytes 15 Adrenergic Signaling in Mouse Myocytes Ultra-rapidly activating delayed rectifier K+ current module. The ultra-rapidly activating delayed rectifier K+ current, IKur, is the substrate of PKA in the extracaveolae compartment in cardiomyocytes. IKur is predominantly encoded by Kv1.5 channels. It is also localized mostly in lipid rafts, which lack caveolin-3, pointing to the extracaveolae compartment. Similar to the Heijman et al. model, we put the IKur current in the extracaveolae compartment. Stimulation of b1-ARs increases the function of IKur. Rapidly recovering transient outward K+ current module. The other substrate of PKA in the extracaveolae Adrenergic Signaling in Mouse Myocytes b1-adrenergic signaling system leads to an increased phosphorylation of PLB by PKA, resulting in an increase in the SERCA pumping rate of Ca2+ from the cytosol to the SR. Dephosphorylation of PLB occurs by protein phosphatase 1 only. Method of Simulation The resulting model contains 141 ordinary differential equations solved by a fourth-order Runge-Kutta method, with different time steps. A relatively small time step of 0.000002 ms is used during the 10 milliseconds after the GSK1278863 initiation of the stimulus current; the rest of the time, the time step is 0.0001 ms. Such small time steps are mainly determined by the very fast activation time constants of ryanodine receptors. For simulation of the cellular behavior without electrical stimulation the time step of 0.1 ms is used. The model is implemented as a program code in FORTRAN 90, which runs on a single processor under SUSE Linux 11 on a Dell Precision Workstation T3500 with six-core Intel Xeon CPU W3670. Simulation of one second of the PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19639073 activity of an electrically stimulated cell runs approximately 3 minutes on this workstation. All model equations, model parameters, and initial conditions are given in Appendix S1. The model is developed for a room temperature of 25uC. Steady-state initial conditions were obtained by Adrenergic Signaling in Mouse Myocytes 18 Adrenergic Signaling in Mouse Myocytes obtained with 200-ms pulses from a holding potential of 2100 mV to +40 mV at stimulation frequency 0.02 Hz. Panel B: Experimental data on a relative increase in IKur current obtained by Yue et al. from canine atrial myocytes at different concentrations of isoproterenol. Corresponding simulation data with our model on relative increase in IKur are shown by a solid line. Simulation data is obtained with 4.5-s pulses from a holding potential of 290 mV to 0 mV after 800-s exposure to different concentrations of isoproterenol. Panel C: Experimental and simulated data on current-voltage relationships for IKur current. Experimental data for control conditions and those obtained after application of 1 mM isoproterenol are shown by unfilled and filled circles, respectively. Simulated data for control conditions are shown by a solid line, and 1 mM isoproterenol simulations are shown by a dashed line. Simulated currents are obtained by 4.5-s depolarizing pulses to between 280 and +50 mV from a holding potential of 290 mV. Panel D: Experimental time course of the relative decrease in the rapid