Figure 1.

(A) A cartoon showing the structure of a HCN channel. HCN channels are tetramers (upper panel). In the lower panel, only two subunits are shown. Each subunit contains the voltage-sensitive (VSD), formed by S1–S3 transmembrane segments (yellow) and by the S4 voltage sensor segment (pink). The pore domain (PD) shown in red is formed by S5-S6 transmembrane segments and the S5-S6 loop. The C-terminus includes the C-linker (green) and the cyclic nucleotide binding domain (CNBD) (orange). The N-terminus contains the HCND (light green). Adapted from Baruscotti et al. (2022) © 2022 European Biophysical Societies’ Association (EBSA). (B) The HCN4 CryoEM structure shows a clear representation by exhibiting only two of the four subunits. Each subunit has six transmembrane-spanning domains that are important for voltage sensing (S1–S4, shown in blue) and pore creation (S5–S6, shown in green). The C-linker (shown in yellow) and the CNBD (displayed in orange) are both found in the C-terminus and aid in the response to cyclic nucleotides. Adapted from Peters et al. (2022) © 2022 Peters, Singh, Bankston and Proenza. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. (C) The arrangement of the four known HCN isoforms (1–4) is illustrated, indicating the locations of the six transmembrane segments (S1–S6) and CNBD. Different isoforms of HCN channels share significant structural similarity in their core regions like the transmembrane segments (S) and CNBDs, but exhibit notable variations in the N and C termini. Adapted from Viscomi et al. (2001) Open Access [Attribution 4.0 International (CC BY 4.0)].