Voltage Sensing In Hyperpolarization Activated Cyclic Nucleotide Gated (Hcn) Channels

The voltage-sensing domains (VSDs) of HCN channels have topologies similar to other voltage-dependent ion channels, including a series of positively charged residues in their S4 helix that are predicted to move with the same directionality as in other channels. However, HCN channels activate very slowly at hyperpolarized potentials. Intriguingly, despite identical S4 and S4-S5 linkers between mammalian isoforms, HCN1-4 activate with different voltage-dependencies and gating kinetics. Here we begin to examine the molecular details of VSD movement in HCN channels through molecular dynamics simulations. Although the gating charge of sea urchin HCN (spHCN) channels has been estimated to be very small compared to that of Kv channels, our data indicates this is obtainable by a similar displacement of the S4 helix. We also compare gating charge estimates of human HCN isoforms, which have been experimentally unattainable to date. Lastly, we examine key interactions between isoforms that may underlie differences in the voltage-gating and kinetics.