1.A.1.5.2
Hyperpolarization-activated and cyclic nucleotide-gated K⁺ channel, HCN (bCNG-1) (P_Na⁺/P_K⁺ ≈ 0.3). The human orthologue (O88703) is 863 aas in length and also catalyzes mixed monovalent cation currents K⁺:Na⁺= 4:1 (Lyashchenko and Tibbs et al., 2008). Biel et al. (2009) presented a detailed review of hyperpolarization-activated cation-channels. They are inhibited by nicotine and epibatidine which bind to the inner pore (Griguoli et al., 2010). They control cardiac and neuronal rhythmicity. HCN channels contain cyclic nucleotide-binding domains (CNBDs) in their C-terminal regions, linked to the pore-forming transmembrane segment with a C-linker. The C-linker couples the conformational changes caused by the direct binding of cyclic nucleotides to the HCN pore opening. Cyclic dinucleotides antagonize the effect of cyclic nucleotides in HCN4 but not in HCN2 channels. Interaction of the C-linker/CNBD with other parts of the channel appears to be necessary for cyclic-dinucleotide binding in HCN4 channels (Hayoz et al. 2017). A conformational trajectory of allosteric gating of the human cone photoreceptor cyclic nucleotide-gated channel has been documented (Hu et al. 2023).  The voltage-sensor rearrangements, directly influenced by membrane lipid domains, can explain the heightened activity of pacemaker HCN channels when localized in cholesterol-poor, disordered lipid domains, leading to membrane hyperexcitability and diseases (Handlin and Dai 2023).  Opioid-induced hyperalgesia and tolerance are driven by HCN ion channels (Han et al. 2024). It acts as a chaperone that facilitates biogenesis and trafficking of functional transporters heterodimers to the plasma membrane. It forms heterodimers with SLC7 family transporters (SLC7A5, SLC7A6, SLC7A7, SLC7A8, SLC7A10 and SLC7A11), a group of amino-acid antiporters (Parker et al. 2021). Heterodimers function as amino acids exchangers, the specificity of the substrate depending on the SLC7A subunit. Heterodimers SLC3A2/SLC7A6 or SLC3A2/SLC7A7 mediate the uptake of dibasic amino acids (Bröer et al. 2000).  The intersubunit interface of the C-linker region regulates the gating polarity of voltage-gated ion channels (Lin et al. 2024).

---