1.A.1.5.11
Hyperpolarization-activated cyclic nucleotide-gated (HCN) inward current-carrying cationic channel, I(f), (HCN2/HCN4) (Ye and Nerbonne, 2009).  Functional interactions between the HCN2 TM region and C-terminal region govern multiple CNB fold-mediated mechanisms, implying that the molecular mechanisms of autoinhibition, open-state trapping, and Quick-Activation include participation of TM region structures (Page et al. 2020). Rhythmic activity in pacemaker cells, as in the sino-atrial node in the heart, depends on the activation of HCN channels. As in depolarization-activated K⁺ channels, the fourth transmembrane segment S4 functions as the voltage sensor in hyperpolarization-activated HCN channels (Wu et al. 2021). S4 in HCN channels moves in two steps in response to hyperpolarizations, and the second S4 step correlates with gate opening (Wu et al. 2021). It is a nuclear hormone receptor that binds estrogens with an affinity similar to that of ESR1/ER-alpha, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (Koyama et al. 2010). It may lack ligand binding ability and has no or only very low ERE binding activity, resulting in the loss of ligand-dependent transactivation ability. Male moujse ejaculation drives sexual satiety and selectively activates Esr2neurons in the BNSTpr of both sexes (Zhou et al. 2023).  Changes in binding affinity, rather than changes in cAMP concentration, can modulate HCN channels (Porro et al. 2024).  HCN2 deficiency correlates with memory deficits and hyperexcitability of dCA1 pyramidal neurons in Alzheimer's disease (Zhang et al. 2025).