Key result
In HCN channels, the S4 voltage sensor moves in two steps in response to hyperpolarizations, with the second step correlating with gate opening and the creation of an intracellular crevice.
Why the study?
How the inward movement of the fourth transmembrane segment S4 in hyperpolarization-activated HCN channels at hyperpolarized voltages couples to channel opening is not understood.
S4 voltage sensors in HCN channels move in two distinct steps during hyperpolarization, with the second step being responsible for opening the channel gate, providing mechanistic insights into pacemaker channel function.
channels, the fourth transmembrane segment S4 functions as the voltage sensor in hyperpolarization-activated HCN channels. But how the inward movement of S4 in HCN channels at hyperpolarized voltages couples to channel opening is not understood. Using voltage clamp fluorometry, we found here that S4 in HCN channels moves in two steps in response to hyperpolarizations and that the second S4 step correlates with gate opening. We found a mutation in sea urchin HCN channels that separate the two S4 steps in voltage dependence. The E356A mutation in S4 shifts the main S4 movement to positive voltages, but channel opening remains at negative voltages. In addition, E356A reveals a second S4 movement at negative voltages that correlates with gate opening. Cysteine accessibility and molecular models suggest that the second S4 movement opens up an intracellular crevice between S4 and S5 that would allow radial movement of the intracellular ends of S5 and S6 to open HCN channels.
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Wu et al. (2021) studied HCN channel gating mechanism. E356A mutation and voltage clamp fluorometry vs. Wild-type spHCN channels was evaluated on S4 voltage sensor movement and channel opening. In HCN channels, the S4 voltage sensor moves in two steps in response to hyperpolarizations, with the second step correlating with gate opening and the creation of an intracellular crevice.
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