Expression of single isoforms in heterologous systems such as human embryonic kidney (HEK) cells, Chinese hamster ovary (CHO) cells and Xenopus oocytes yield homotetrameric channels able to generate ion currents with properties similar to those of the native If/Ih current, but with quantitative differences in the voltage-dependence, activation/deactivation kinetics and sensitivity to the nucleotide cyclic AMP (cAMP): HCN1 channels have a more positive threshold for activation, faster activation kinetics, and a lower sensitivity to cAMP, while HCN4 channels are slowly gating and strongly sensitive to cAMP.
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.
[6] HCN channels are regulated by both intracellular and extracellular molecules[clarification needed], but most importantly, by cyclic nucleotides (cAMP, cGMP, cCMP).
[4] In addition to their proposed roles in pacemaking rhythmic or oscillatory activity, HCN channels may control the way that neurons respond to synaptic input.
Initial studies suggest roles for HCN channels in sour taste, coordinated motor behavior and aspects of learning and memory.
[18] HCN channels have also been observed in the retrotrapezoid nucleus (RTN), a respiratory control center that responds to chemical signals such as CO2.