FIGURE 6.

(A and B) Voltage dependence of the contribution of CDI to total inactivation for two different times (early, t_early; late, t_late) after application of a voltage step to varying potentials from a holding potential of −80 mV. The plotted values are the ratio of current decay recorded with Ca²⁺ as the charge carrier relative to that recorded with Ba²⁺ as the charge carrier. Experiments (from Findlay (55), with permission) (▪) were conducted at room temperature (23°C) and simulations (solid line) at 37°C; values of t_early and t_late were adjusted for 37°C in the simulations. (Experiment: t_early = 20 ms, t_late = 200 ms; Simulation: t_early = 8 ms, t_late = 80 ms). (C–F) Relative contributions of Ca²⁺ through the channel and Ca²⁺ released from the SR to total CDI during a voltage step. (C) Trace 3 (thin curve) shows simulated I_Ca(L) in the absence of Ca²⁺-dependent inactivation, corresponding to current carried by monovalent cations or Ba²⁺, for a voltage step from −80 to −10 mV. Trace 2 (medium curve) shows I_Ca(L) with Ca²⁺ as the charge carrier (hence with Ca²⁺-dependent inactivation) but with no Ca²⁺ release from the SR (I_rel = 0) for a voltage step from −80 to 0 mV (the 10-mV difference in test potential compared to trace 3 is to reproduce the experimental protocol in panel D for comparison). Trace 1 (thick curve) shows I_Ca(L) for the same square pulse with Ca²⁺ as the charge carrier and SR calcium release intact. (D) Experimental recordings of I_Ca(L) in human atrial myocytes measured at room temperature. Trace 3 is the current through the channel utilizing monovalent cations as the charge carrier tested with a voltage step from −80 to −10 mV. Trace 2 shows I_Ca(L) with Ca²⁺ as the charge carrier but with SR release blocked with ryanodine during a voltage step from −80 to 0 mV. Trace 3 shows I_Ca(L) with Ca²⁺ as the charge carrier and SR release intact for the same voltage step. (E) Simulated fraction of Ca²⁺-induced inactivation that results from Ca²⁺ released from the SR (gray) or from Ca²⁺ entering via I_Ca(L) (black). The formula for determining the relative contribution is from Sun et al. (8) where the I_Ca(L) dependent fraction = (trace3 − trace2)/(trace3 − trace1) and the SR dependent fraction = (trace2 − trace1)/(trace3 − trace1). (F) Experimental fractional contribution of I_Ca(L)-dependent (black) and SR dependent (white) Ca²⁺-induced inactivation of I_Ca(L). Experimental curves in panels D and F are reproduced from Sun et al. (8), with permission.