Theoretical predictions of RYR2 modulation by free Ca²⁺ in the SR lumen. The calculations are derived from application of the luminal-triggered feedthrough model to the physiological context as described in the Discussion (Physiological implications). (A and B) The effect of various factors on the opening frequency, F_o, normalized to their values at [Ca²⁺]_L = 1 mM and mean open time, τ_o, of RYRs. See below for the absolute values of F_o at [Ca²⁺]_L = 1 mM for each condition. Diastolic conditions ([Ca²⁺]_C = 0.1 μM) and systole ([Ca²⁺]_C = 1 μM; in B both lines coincide). The contribution of various factors is seen by setting associated parameters to zero (dashed lines). For Ca²⁺ feedthrough, the Ca²⁺ current was set to zero (I_Ca = 0). Elimination of luminal Mg²⁺ inhibition ([Mg²⁺]_L = 0 and 0.2 mM; they coincide with the thick line in B). Elimination of cytoplasmic Mg²⁺ inhibition from the I₁- and A- sites ([Mg²⁺]_C = 0) and from the I₁-site only (–I₁). (C and D) The effects of perturbing A- and L-sites on SR load dependence of F_o and τ_o under diastolic conditions (solid line, K_ACa = 1.2 μM and K_LCa = 40 μM). Dashed lines show the effect of increasing Ca²⁺ sensitivities of either the A-site (K_ACa = 0.6 μM) or L-site (K_LCa = 15 μM; in B this coincides with the solid line). (A and B) [Ca²⁺]_C = 0.1 μM (normalizing factor, 3.0 × 10⁻⁴); [Ca²⁺]_C = 1 μM (normalizing factor, 2.9 × 10⁻²); [Mg²⁺]_C = 0 (normalizing factor, 1.07); [Mg²⁺]_L = 0 (normalizing factor, 1.2 × 10⁻³); [Mg²⁺]_L = 0.2 (normalizing factor, 0.8 × 10⁻³); -I₁ site (normalizing factor, 2.9 × 10⁻⁴); I_Ca = 0 (normalizing factor, 1.6 × 10⁻⁴).