Cooperative binding model of SERT. (A) Kinetic scheme of the model. k_on(S_out) = 10⁷ M⁻¹ s⁻¹ (5-HT/PAL-1045/1046/287), 2 × 10⁶ M⁻¹ s⁻¹ (p-chloroamphetamine); k_off(S_out) = 10 s⁻¹ (5-HT, p-chloroamphetamine), 0.5 s⁻¹ (PAL-1045), 15 s⁻¹ (PAL-1046/287); k_on(S_in) = 10⁶ M⁻¹ s⁻¹ (5-HT/PAL-1046/287), 7 × 10⁷ M⁻¹ s⁻¹ (PAL-1045), 10⁵ M⁻¹ s⁻¹ (p-chloroamphetamine); k_off(S_in) = 1 s⁻¹ (5-HT), 3.5 s⁻¹ (PAL-1045), 1.5 s⁻¹ (PAL-1046/287), 0.5 s⁻¹ (p-chloroamphetamine). α values: 5-HT, 30; PAL-1045, 25; PAL-1046/287, 20; p-chloroamphetamine, 1. ω values: 200 for all substrates. (B) Simulated current traces of 30 µM 5-HT, 30 µM PAL-1045, and 30 µM p-chloroamphetamine. This panel reproduces experimental data described in Bhat et al. (2017) and Sandtner et al. (2014). (C and D) Simulation of Na⁺ dependence of peak current recovery at varying extracellular (C) and intracellular (D) Na⁺ concentrations. This simulation reproduces data shown in Figs. 1 and 2 and partly in Bhat et al. (2017). The time course of recovery after substrate application was modeled as the time course of return to ToClNa after substrate application. For the data points shown for p-chloroamphetamine, k_fast values obtained from the biexponential fits were used (see Materials and methods).