Anionic lipids unlock the gate of pacemaker channels

Hyperpolarization-activated and cyclic nucleotide-modulated channels (HCN) determine pacemaking activity in the heart and brain. Signaling lipids PIP and phosphatidic acid (PA) potentiate HCN activity, but the mechanisms are unknown, since functional studies were performed in cells, with limited control over membrane composition. Here we use SthK, a bacterial homolog of HCN, to investigate lipid-modulation in molecular detail. SthK activity depends on the charge of lipids as revealed by flux-assays and single-channel recordings in defined lipid environments.