Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are integral membrane proteins that serve as nonselective voltage-gated cation channels in the plasma membranes of heart and brain cells. HCN channels are sometimes referred to as pacemaker channels because they help to generate rhythmic activity within groups of heart and brain cells. HCN channels are activated by membrane hyperpolarization, are permeable to  and , and are constitutively open at voltages near the resting membrane potential. HCN channels are encoded by four genes (HCN1, 2, 3, 4) and are widely expressed throughout the heart and the central nervous system.
The current through HCN channels, designated I or I, plays a key role in the control of cardiac and neuronal rhythmicity and is called the pacemaker current or "funny" current. 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 I/I 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. HCN2 and HCN3 have intermediate properties.