Identification of a distinct lock system for cAMP binding in HCN channels

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are the molecular correlate of the Ih/If current, which plays a key role in controlling rhythmic activity in pacemaker cells. HCN channels are activated by voltage and regulated by direct binding of cAMP to their cytoplasmic C-terminal Cyclic Nucleotide Binding Domain (CNBD). The Cryo-EM structure of HCN1 revealed the presence of two helices, D and E, that fold upon cAMP binding and establish a contact to the upstream CNBD. We thus investigated the hypothesis that helices D and E regulate cAMP affinity.