Hyperpolarization-activated and cyclic nucleotide–gated (HCN) channels belong to the superfamily of voltage-gated K (Kv) and cyclic nucleotide–gated (CNG) channels. HCN channels are thought to consist of four either identical or non-identical subunits that are integrally embedded in the cell membrane to create an ion-conducting pore. Each subunit comprises six membrane-spanning (S1–6) domains which include a putative voltage sensor (S4) and a pore region between S5 and S6 carrying the GYG triplet signature of K-permeable channels, and a cyclic nucleotide-binding domain (CNBD) in the C-terminus. HCN isoforms are highly conserved in their core transmembrane regions and cyclic nucleotide binding domain (80–90% identical), but diverge in their amino- and carboxy-terminal cytoplasmic regions.
HCN channels are regulated by both intracellular and extracellular molecules, but most importantly, by cyclic nucleotides (cAMP, cGMP, cCMP). Binding of cyclic nucleotides lowers the threshold potential of HCN channels, thus activating them. cAMP is a primary agonist of HCN2 while cGMP and cCMP may also bind to it. All three, however, are potent agonists.