Hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) and Hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) (HCN4 and HCN2)

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are a family of nonselective voltage-gated cation channels expressed in the heart and nervous system. Among four known isoforms (HCN1–4), HCN4 is the dominant cardiac pacemaker isoform, generating the I_f (\"funny\") current that controls the spontaneous electrical activity of the sinoatrial node, and thus, heart rhythm[1][2][3]. HCN2 is highly expressed in both heart and brain, involved in rhythm generation and modulation of excitability[1][2][3][4]. Both channels are activated by hyperpolarization and modulated by cyclic nucleotides (mainly cAMP). Mutations in HCN4 are causative for certain conduction diseases, and both isoforms are targets for therapeutics aimed at heart rate and pain modulation. The channels are tetrameric, each subunit containing six transmembrane domains and an intracellular cyclic nucleotide-binding domain[1][9].

Other names

Hyperpolarization-activated cyclic nucleotide-gated channel 4Hyperpolarization-activated cation channel HCN4Pacemaker channelHyperpolarization-activated cyclic nucleotide-gated channel 2Hyperpolarization-activated cation channel HCN2

Blockade or inhibition of the pacemaker (\"funny,\" I_f or I_h) current in cardiac tissue (for ivabradine)\nInhibition reduces heart rate by slowing diastolic depolarization in sinoatrial node cells