HCN channel

Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are intermembrane proteins that serve as nonselective ligand-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 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_f or I_h, 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 yields homotetrameric channels able to generate ion currents with properties similar to those of the native I_f/I_h current, but with quantitative differences in the voltage-dependence, activation/deactivation kinetics and sensitivity to the nucleotide cyclic AMP (cAMP): HCN1 channels show the more positive threshold for activation, the fastest activation kinetics, and the lowest sensitivity to cAMP, while HCN4 channels are slowly gating and strongly sensitive to cAMP. HCN2 and HCN3 have intermediate properties.

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