Hyperpolarization-activated cyclic-nucleotide-gated (HCN) ion channels are found in rhythmically firing cells in the brain and in the heart1, where the cation current through HCN channels (called Ih or If) causes these cells to fire repeatedly2. These channels are also found in non-pacing cells, where they control resting membrane properties, modulate synaptic transmission, mediate long-term potentiation, and limit extreme hyperpolarizations3-7. HCN channels share sequence motifs with depolarization-activated potassium (Kv) channels, such as the fourth transmembrane segment S48,9. S4 is the main voltage sensor of Kv channels, in which transmembrane movement of S4 charges triggers the opening of the activation gate10-12. Here, using cysteine accessibility methods10-12, we investigate whether S4 moves in an HCN channel. We show that S4 movement is conserved between Kv and HCN channels, which indicates that S4 is also the voltage sensor in HCN channels. Our results suggest that a conserved voltage-sensing mechanism operates in the oppositely voltage-gated Kv and HCN channels, but that there are different coupling mechanisms between the voltage sensor and activation gate in the two different channels.
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