HCN Channel

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.

An Overview of HCN Channel

Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels is a unique ion channel for mammals by the name of Santoro et al in 1998. HCN study originated in 1976 and is a special funny current/queer current (If/Iq) found in the study of rabbit sinoatrial node cells by Noma et al. The HCN channel has intrinsic hyperpolarization-activated cation current (Ih) activity, which shows that it plays an important role in the biological cell pacing, which is dependent on the cardiac pacing and nervous system activity.

Major types of HCN Channel

There are four subtypes (HCN1-HCN4) in the HCN pathway in mammals, and these four subtypes form different homologous or heterogeneous dimer, with different biophysical properties. The four subtypes of HCN channel are mainly located in the cerebral cortex, hippocampus, brainstem, spinal cord and dorsal root ganglion (DRG). Gradient expression of HCN1 pathway in pyramidal bundle and thalamus reticular neurons in cortex and hippocampus CA1 region. The HCN2 channel is distributed almost throughout the body, in the thalamus and brainstem. The nucleus and the small dorsal root ganglia are the most distributed places. The expression of HCN3 in the HCN channel family is very low, only in the olfactory receptor and the hypothalamus. HCN4 expression is in olfactory receptors and thalamus nuclei.

Inhibition of HCN Channel

Given that the HCN channel is closely related to many diseases, it is possible to use it as a target, but because the HCN channel is widely distributed, the channel blockers are all non-selective subtypes inhibitors. Falipamil, , are voltage dependent, which are regarded as HCN channel door regulator.

HCN Channel and Diseases

HCN channel can be used to treat pain-related illnesses such as inflammation or neurological pain. At the same time, the HCN channel can regulate epilepsy disease. In addition, the HCN channel plays an important role in the establishment of a pacemaker in vertebrates to treat heart rate-related diseases. Also, HCN channels are used for the treatment of gastrointestinal dysfunction. All in all, the HCN channel is related to many diseases.


1. Jung, S., Warner, L. N., Pitsch, J., Becker, A. J., & Poolos, N. P. (2011). Rapid loss of dendritic HCN channel expression in hippocampal pyramidal neurons following status epilepticus. Journal of Neuroscience, 31(40), 14291-14295.

2. Kanyshkova, T., Meuth, P., Bista, P., Liu, Z., Ehling, P., Caputi, L., ... & Budde, T. (2012). Differential regulation of HCN channel isoform expression in thalamic neurons of epileptic and non-epileptic rat strains. Neurobiology of disease, 45(1), 450-461.

3. Noam, Y., Bernard, C., & Baram, T. Z. (2011). Towards an integrated view of HCN channel role in epilepsy. Current opinion in neurobiology, 21(6), 873-879.

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