Fig. 6.

Voltage gating scheme for the CNBD family of channels. (A, Top) A unified state model for the CNBD family of ion channels. (A, Middle) A structural map highlighting the key elements involved in determining gating polarity in HCN1 channels. Only three out of four monomers are shown for clarity. The structural elements are colored according to their influence on each of the states shown in the unified gating model. The color scheme depicting which states are stabilized or destabilized by a particular element is shown below the structure. (B) Cartoon representations and models for several selected chimeras and mosaics. Bolded arrows indicate transitions that are favored by introduction of the HCN-like S4–S5 interface (HHHE*H), removal of the C terminus (HHHE*ΔC), or pore mutations near the gate (HHHE*ΔC-SD). (C) Simulated current traces from the model in response to the same pulse protocol applied in the electrophysiological recordings for each construct. Parameters for simulations can be found in SI Appendix, Table S1. (D) Probability vs. voltage curves for each state in the model measured as the probability of occupancy of each state over the final 10 ms of each test pulse. Probability curves for the hyperpolarized open state are colored red, the closed state is in blue, depolarized open state is in black, and inactivated state is in gray.