Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function

cAMP regulation of ion channels controls higher brain functions, such as sleep, memory, and cognition. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are activated by the direct binding of cAMP to their cytoplasmic tail and inhibited by the neuronal β-subunit tetratricopeptide repeat-containing Rab8b interacting protein (TRIP8b), which prevents cAMP binding. Understanding the molecular mechanisms of regulation of this family of ion channels is critical because it pertains to the physiological processes and diseases associated with dysfunctions in the HCN current. Here, we explain the dual regulatory system of HCN2 channels in atomic detail. cAMP and TRIP8b do not compete for the same binding site on the HCN2 cytoplasmic tail; rather, they exert their mutual competition by promoting and stabilizing two different conformational states of the protein.