A family of hyperpolarization-activated channels selective for protons

Significance We discovered a subfamily of voltage-gated ion channels, called HCN-like channels, consisting of two members, HCNL1 and HCNL2. In contrast to classic pacemaker HCN channels in the heart and brain, HCNL1 conducts protons rather than potassium or sodium ions. The pore domain, which exists in most voltage-gated channels, is nonconducting. Instead, protons permeate the channel via the voltage-sensing domain involving the S4 motif. Key to proton conduction is a methionine residue that interrupts the regularly spaced series of arginine residues in S4. We show that fish sperm use this unusual ion pathway to create a hyperpolarization-gated proton influx that counterbalances an alkaline-activated K + channel.