Modeling acidosis on the I-V curve for peak I_Ca,L. To simulate the overall effects of acidosis on the I-V curve, we used the mean activation parameters (V_1/2, k) shown in Table S1 (without BAPTA) and a modification of the equation of Hanck and Sheets (1992), $ICa,L=Gmax(Vm−Vrev)/[1+exp(Vm−V1/2)]/k,$ as a simplified model for the voltage dependence of peak I_Ca,L. The term, G_max(V_m−Vrev), was replaced by a GHK equation for I_Ca,L, similar to that described by Luo and Rudy (1994):$I−Ca,L=I−Ca+I−CsI−s=Ps zs2 Vm F2RT [S]i exp(zs Vm F)/(RT)−[S]oexp(zs Vm F)/(RT)−1,$ where $I−Ca,L$ is the sum of peak current carried by calcium (⁠$I−Ca,L$⁠) and cesium (⁠$I−Cs$⁠), and z, F, R, and T have their usual meanings. P_Ca under control conditions was taken as 5.4 × 10⁻⁴ cm/sec, and P_Cs was assumed to be similar to P_K at 2.7 × 10⁻⁷ cm/sec (Luo and Rudy, 1994). [Ca²⁺]_o was 1.1 mM and [Ca²⁺]_i was assumed to be 100 nM under control conditions. Raising [Ca2+]_i to as high as 1 µM has a negligible effect on the calculated I_Ca,L reversal potential, so [Ca²⁺]_i was kept at 100 nM in all simulations. [Cs⁺]_i was assumed to be equal to that in the pipette at 133 mM, and [Cs⁺]_o was 4.4 mM. The results for each type of acidosis simulation are summarized in each panel. The cartoon figures depict qualitatively the effects of each type of acidosis on the voltage profile within the sarcolemma (black, control; blue, acidosis) and channel permeability. A larger sarcolemmal surface potential is shown on the inner membrane surface in accord with previous reports in cardiac cells (Post et al., 1988). All calculations in this figure were made according to Eqs. 2 and 3. The control-simulated I-V curves in all panels are shown in black. (A) Extracellular acidosis. Shifting the V_1/2 of activation (d_∞) by the measured amount of 48.5% to the right moved the curve downward and to the right (blue), as indicated by the red arrow. Also included is the measured 13.6% reduction in k, which had only a small effect on the curve. The red curve includes the same changes in V_1/2 and k, along with a 16.6% reduction in P_Ca. The latter was obtained by systematically varying P_Ca until the percent drop in current at 0 mV, compared with control, matched the 30% decline measured experimentally (Fig. 4 B, left). The cartoon depicts qualitatively the actions of external protons to both decrease P_Ca (dashed red arrow) and screen/bind external surface charge (red circle with “−” and blue lines in membrane). (B) Intracellular acidosis. Shifting the V_1/2 of activation by the measured amount of −112.0% to the left moved the curve upward and to the left (blue), as indicated by the red arrow. Also included is the measured 20.0% reduction in k, which had only a small effect on the curve. The red I-V curve includes the same changes in V_1/2 and k, along with a 24.0% reduction in P_Ca. The latter was obtained by systematically varying P_Ca until the percent drop in current at +20 mV, compared with control, matched the 26% current decline measured experimentally (Fig. 4 B, left). The cartoon illustrates qualitatively the actions of intracellular protons to increase [Ca²⁺]_i and screen/bind internal surface charge (red circle with “+” and blue lines in membrane). It also shows the action of increased [Ca²⁺]_i to decrease channel permeability (dashed red arrow). (C) Combined acidosis. A left shift in the V_1/2 of activation by the measured amount of 24.7% moved the curve upward and to the left (blue). Also included is the 11.1% decrease in k, which had only a small effect on the curve. The red curve includes the same changes in V_1/2 and k, along with a 16.6% reduction in P_Ca. The latter was obtained by systematically varying P_Ca until the percent drop in current at +20 mV, compared with control, matched the 17% current decline measured experimentally (Fig. 4 C, left). The cartoon illustrates qualitatively the proposed actions of combined acidosis on [Ca²⁺]_i, channel permeability, and the voltage drop across the sarcolemma (blue lines in membrane).