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 flowing through HCN channels, designated If or Ih, plays a key role in the control of cardiac and neuronal rhythmicity ("pacemaker 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 If/Ih 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.
Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels belong to the superfamily of voltage-gated K+ (Kv) and cyclic nucleotide-gated (CNG) channels. HCN channels are thought to consist of four either identical or non-identical subunits that are integrally embedded in the cell membrane to create an ion-conducting pore. Each subunit comprises six membrane-spanning (S1–6) domains which include a putative voltage sensor (S4) and a pore region between S5 and S6 carrying the GYG triplet signature of K+-permeable channels, and a cyclic nucleotide-binding domain (CNBD) in the C-terminus. HCN isoforms are highly conserved in their core transmembrane regions and cyclic nucleotide binding domain (80–90% identical), but diverge in their amino- and carboxy-terminal cytoplasmic regions. The ribbon model to the right depicts HCN1.
Function in the Heart
HCN4 is the main isoform expressed in the sinoatrial node, but low levels of HCN1 and HCN2 have also been reported. The current flowing through HCN channels, called the funny current or pacemaker current (If), plays a key role in the generation and modulation of cardiac rhythmicity.
Function in the Nervous System
All four HCN subunits are expressed in the brain. In addition to their proposed roles in pacemaking rhythmic or oscillatory activity, HCN channels may also control the way that neurons respond to synaptic input. Initial studies suggest roles for HCN channels in sour taste, coordinated motor behavior and aspects of learning and memory. Clinically, there is evidence that HCN channels play roles in epilepsy and neuropathic pain.
||This section possibly contains original research. (August 2008)|
HCN Channels and the Prefrontal Cortex Stimulation of a certain receptor in the prefrontal cortex known as the alpha2A-adrenoceptor (also known as the alpha-2A adrenergic receptor) has been shown to improve working memory, or the brain’s capacity to retain, manipulate and utilize information relevant to one’s surroundings. This function of the brain is critical to normal cognitive performance in everyday life. Working memory impairment can dramatically affect cognitive function, and it is a symptom of many neurological diseases, including schizophrenia. Thus the alpha2A-adrenoceptor is the target of current research seeking to prevent or counteract working memory impairment. The Arnsten Lab at Yale University recently found that HCN channels serve as the intracellular mechanism through which stimulation of alpha2A-adrenoceptors improves working memory. [results reviewed in Robbins & Arnsten 2009]
The lab found that directly closing HCN channels with the drug ZD7288 strengthened working memory on the cellular level in much the same manner as stimulation of alpha2A-adrenoceptors themselves. By directly inhibiting HCN channels in vivo?, either with the drug ZD7288 or viral knockdown of HCN1 expression, the Arnsten lab was able to improve working memory in rats. Interestingly, both alpha2A-adrenoceptors and HCN channels were observed to be co-localized on small projections of neuron membrane known as dendritic spines. These findings suggest that dendritic spines are the structures within which HCN channels and alpha2A-adrenoceptors interact to affect working memory.
The Arnsten Lab hypothesized a role for HCN channels in working memory impairment. If, because of neurological disease, HCN channels in dendritic spines are over-active, they would prevent electrical impulses from traveling through the spine. Too many open HCN channels would increase the conductivity of the membrane to such an extent than many impulses entering the neuron through the spine would effectively be shunted out of the cell. This would prevent information from being reliably passed between the networks of neurons that form the cellular basis of working memory, causing working memory impairment. Therefore, drugs that are capable of closing HCN channels would strengthen the connectivity of the networks of neurons necessary of working memory, and ameliorate the working memory impairment observed in diseases like schizophrenia. On a side note, ZD7288 is not being considered as a possible drug candidate because it is unable to cross the blood–brain barrier, and thus cannot be administered systemically. However, other drugs such as the alpha2A-adrenoceptor agonist guanfacine are capable of indirectly closing HCN channels, and could prove to be useful treatments for working memory impairment.
HCN Channels, Nicotine depdendence and smoking cessation HCN channels have also been implicated to be important for nicotine dependence and withdrawal. Neurons in the medial habenula of the midbrain show spontaneous HCN channel dependent action potential activity of 2-10 Hz. Block of HCN channel mediated pacemaker activity in medial habenula neurons in vivo, results in a nicotine withdrawal-like phenotype. 
- Luthi A, McCormick DA. 1998. Neuron. H-current: properties of a neuronal and network pacemaker. Vol. 21. pp 9-12.
- Kaupp UB, Seifert R. Molecular diversity of pacemaker ion channels (2001)Annu Rev Physiol. 63:235-57. Review.
- Notomi T, Shigemoto R (2004) Immunohistochemical localization of Ih channel subunits, HCN1-4, in the rat brain. J Comp Neurol 471: 241-276.
- Wahl-Schott C, Biel M. (2009) HCN channels: structure, cellular regulation and physiological function. Cell Mol Life Sci. 2009 Feb;66(3):470-94. Review
- Baruscotti, M., Bucchi, A., DiFrancesco, D. (2005). Physiology and pharmacology of the cardiac pacemaker ("funny") current. Pharmacology & Therapeutics, 107, 59-79
- Santoro B, Tibbs GR. (1999) The HCN gene family: molecular basis of the hyperpolarization-activated pacemaker channels. Ann N Y Acad Sci. Apr 30;868:741-64. Review
- Swiss-Prot entry
- Larsson, H. P. (2010). "How is the heart rate regulated in the sinoatrial node? Another piece to the puzzle". The Journal of General Physiology 136 (3): 237–241. doi:10.1085/jgp.201010506. PMC 2931147. PMID 20713549.
- Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Dugue A, Vijayraghavan S, Brennan A, Dudley A, Nou E, Mazer JA, McCormick DA, Arnsten AF. 2007. Cell. alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Vol. 129. pp 1-14.
- Robbins TW, Arnsten AFT. 2009. Annual Reviews of Neuroscience. The neuropsychopharmacology of Fronto-executive Function: Monoaminergic Modulation. Vol. 32. pp 267-287.
- Gorlich, A.; Antolin-Fontes, B.; Ables, J. L.; Frahm, S.; Slimak, M. A.; Dougherty, J. D.; Ibanez-Tallon, I. (30 September 2013). "Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons". Proceedings of the National Academy of Sciences 110 (42): 17077–17082. doi:10.1073/pnas.1313103110.
- "Ccyclic Nucleotide Regulated Channels". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.