Side chain interactions in C-terminal S4 helix required for gating polarity of HCN channels

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels contribute to the rhythmic firing of pacemaker neurons and cardiomyocytes. Mutations in HCN channels are associated with cardiac arrhythmia and epilepsy. HCN channels belong to the superfamily of voltage-gated K+ channels, most of which are activated by depolarizations. HCN channels, however, stand out in this family because they are activated by hyperpolarizations. The reversed gating polarity of HCN channels is attributed to a different coupling between the voltage-sensing domain (VSD) and the pore domain (PD).