Hyperpolarization-activated cyclic nucleotide-gated channel (HCN1-4) (HCN)

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are a family of four isoforms (HCN1-4) that function as non-selective cation channels activated by membrane hyperpolarization [UniProt: P59158]. They are often referred to as 'pacemaker' channels because they generate the 'funny' current (If) in the heart and the 'h' current (Ih) in the brain, which are critical for rhythmic activity and resting membrane potential regulation [PubMed: 23319474]. HCN4 is the dominant isoform in the cardiac sinoatrial node, making it the primary clinical target for heart rate modulation [PMC: 3545547]. The drug ivabradine is the only FDA-approved inhibitor of these channels, used to treat chronic heart failure and stable angina by selectively slowing the heart rate without affecting myocardial contractility [StatPearls: Ivabradine]. Beyond the heart, HCN1 and HCN2 are highly expressed in the central nervous system, where they influence neuronal excitability and are implicated in epilepsy and neuropathic pain [PMC: 3089710]. Side effects of HCN inhibition, such as visual phosphenes, arise from off-target effects on HCN1 channels in the retina [PubMed: 20956601].

Other names

Funny current channelPacemaker channelHCN1HCN2HCN3HCN4Hyperpolarization-activated cation channelHACBCNG

Selective inhibition of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, specifically the If current in the sinoatrial node, which reduces the slope of diastolic depolarization and slows the heart rate.