Figure 2. An allosteric mechanism underlying the CDI reduction.

(A) Diagram representing an allosteric model of CDI. Channels transition from mode 1 with high P_O, to mode Ca²⁺ with lower P_O, in response to Ca²⁺ entry. Equilibrium constants Q_EFF (concerted movement of S1–S4 segments), L (S6 movement), and a (mutation effect) govern transitions between open and closed channel configurations¹⁴,³⁸, while the effective equilibrium constant J(Ca²⁺) governs entry into mode Ca²⁺. The parameter f (0 < f < 1) scales the P_O in mode Ca²⁺ resulting in CDI. State transitions expected to be effected by the A760G are shaded pink. (B) Total CDI (black), the product of F_CDI (blue) and CDI_max (green), is plotted as a function of ∆∆G_a for the model shown in panel A. The A760G mutation left-shifts voltage activation (∆∆G_a< 0, a > 1), predicting a decrease in CDI due to a decrease in CDI_max. (C) Exemplar Ca²⁺ current traces through WT Ca_V1.3_short channels. Larger current amplitudes (ii, iii) allow a greater influx of Ca²⁺, enhancing entry into mode Ca and thus increasing CDI as compared to diminutive Ca²⁺ currents (i). (D) f₃₀₀ values for individual cells expressing WT Ca_V1.3_short are plotted as a function of current density. The curve saturates at CDI_max ~0.9 (red dashed line). Traces in C correspond to i–iii. (E) Exemplar Ca²⁺ current traces through A760G Ca_V1.3_short channels. Similar to that of WT (C), larger current amplitude increases f₃₀₀ values. (F) Population data representing CDI of A760G Ca_V1.3_short channels. f₃₀₀ values saturate at CDI_max ~0.7 (red dashed line), significantly lower than WT.