Fig 9. TMEM16A activation pathways predicted by Scheme IV.

(A) Time dependent P_C, P_O, P_CCl and P_ClO when [Cl⁻]_o was 140 mM (blue lines) or 30 mM (red lines) while [Ca²⁺]_i and [Cl⁻]_i were 0 M and 40 mM, respectively. Note that P_O was ≈ 0 at both [Cl⁻]. (B) Time dependent P_C, P_CCl, P_CCa, P_ClCCa, P_ClOCa, P_C2Ca, P_O2Ca, and P_ClO2Ca are shown in rectangles coloured according to the colours of the layers of Scheme IV presented in panel C. Left column: [Ca²⁺]_i = 0.2 µM, [Cl⁻]_o/[Cl⁻]_i=140/40 mM. Right column: [Ca²⁺]_i = 0.2 µM, [Cl⁻]_o/[Cl⁻]_i=30/40 mM. P_O, P_ClO, P_OCa, and P_ClC2Ca are not shown for clarity, their values were ≈ 0. P values were calculated by numerically integrating the differential equations (supplemental material) under the following conditions: [Cl⁻]_o =140 mM or 30 mM, [Cl⁻]_i = 40 mM, [Ca²⁺]_i = 0 (A), 0.2 (B) µM, and 20 s pulse to +140 mV followed by repolarization to −60 mV. The set of rate constants listed in Table 2 was used to obtain the time dependence of occupation probability. (C) TMEM16A activation pathways according to probability of occupation. Blue and pink arrows indicate the pathway in the absence of intracellular Ca²⁺ while [Cl⁻]_o was 140 mM or 30 mM, respectively. Black, grey, green and light green arrows indicate the activation pathways when intracellular Ca²⁺ was 0.2 µM while [Cl⁻]_o was 140 mM (black and green lines) or 30 mM (grey and light green lines). [Cl⁻]_i was set at 40 mM. Red button = Ca²⁺, blue donut = Cl⁻.