Human Hyperpolarization Activated Cyclic Nucleotide Gated Ion Channel 4 (HCN4); A Target Enabling Package

HCN4 is one of four hyperpolarisation activated cyclic nucleotide gated ion channels. It is responsible for the pacemaker or funny (If) current in the heart and is required for maintenance of a stable heartbeat. Mutations in HCN4 lead to a number of arrhythmias. HCN4 is the target for the angina drug ivabradine, which reduces HCN4 activity. However, ivabradine is non-selective, affecting all of the four HCN channels. HCN4 is a close homologue of HCN2, which is a target for neuropathic and inflammatory pain treatment. We have solved the structure of HCN4 both in complex with cyclic AMP and without nucleotide. Comparison of our HCN4 structure with that of the related HCN1 channel (86% identity) allows us to suggest ways to design selectivity for small molecule inhibitors between these closely related channels.