Fig. 4: Model I: only the fully open state is conducting, and subunits move independently during desensitization.

a We assume in this model that a single desensitized subunit is enough to shut the pore of the channel, leading to functional desensitization. Moreover, subunits SU3, SU4, and SU5 can undergo a desensitization rearrangement independent of the other subunits. Thus, desensitization rates (δ₃⁺ for SU3, δ⁺ for SU4 and SU5) and recovery rates (δ₃⁻ for SU3, δ⁻ for SU4 and SU5) do not depend on the conformation of the neighboring subunits. b Effect of M3-5′ valine mutations in Model I. Mutations are hypothesized to specifically increase the desensitization rates of the mutated subunits, without altering any other parameter. c–e Representative currents for C^WT (panel c), C⁴ (panel d) and C⁴⁵ (panel e), in black, are compared to the outcome of two distinct simulations. In simulation a (red), the mutation-induced increase in the desensitization rates of SU4 and SU5 is adjusted so that the simulation of single mutants C⁴ and C⁵ broadly fits the experimental data, as seen in panel (d). In simulation b (blue), the mutation-induced increase in the desensitization rates of SU4 and SU5 is adjusted so that the simulation of the double mutant C⁴⁵ accounts for the experimental data, as seen in panel (e). f Bar graph summarizing the experimental data vs the predicted effects of SU4 and/or SU5 mutations on the kinetics of the fast desensitization component in simulations a and b. Experimental data are shown as means (bar graphs) and standard deviations (error bars), with individual data points indicated as circles. For panels c–f note that parameters from simulation a fail at describing the data for the double mutant C⁴⁵, while parameters from simulation b largely overestimate the effect of single mutants. See Supplementary Table 1 for numerical experimental values, the number of cells and number of independent series of experiments; and Supplementary Table 3 for the numerical values of parameters.