Fig. 6: Kinetic modeling of the effect of JNJ-67869386 on desensitization kinetics.

a Qualitative model for channel activation and desensitization in the absence and presence of compound. In the presence of compound, closed-state desensitization and recovery involve only three states, CB, C, and CD (transitions between these states are represented by thick lines). Recovery from (equilibrated) open-state desensitization funnels through the same three states, after an initial rapid transition from OD → CD. Recovery from (unequilibrated) open-state desensitization, i.e., before compound dissociation (OBD → OD) is completed, takes an additional path via CBD (grayed), a pass-through state, as follows: OBD → CBD → CB → C. Arrowed lines indicate irreversible transitions. b Linear kinetic model used for kinetic simulations. Compound-bound desensitized states are excluded from the scheme. c Simulated responses (dashed lines) of the onset of closed-state desensitization overlaid with experimental data from Fig. 3c. d Simulated responses (dashed lines) of recovery from closed-state desensitization overlaid with experimental data from Fig. 3f. e Simulated responses (dashed lines) of onset of and recovery from compound inhibition overlaid with experimental data from Fig. 5a (without steady-state subtraction) and Supplementary Fig. 3. f Simulated responses (dashed lines) of recovery from open-state desensitization overlaid with experimental data from Fig. 4e. g Rate constants used for the simulations. All simulations are performed with the same set of parameter values given in the table (taking into account irreversible transitions as appropriate). For recovery from desensitization, the initial state is set to be CD₃.