Hyperpolarization-activated cyclic nucleotide gated (HCN) channels are proteins that serve as ion channels across the plasma membrane 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. The larger family of HCN channels contains multiple individual channels that differ slightly in their location, structure, and function: HCN1, HCN2, HCN3, and HCN4. HCN1 and HCN2 channels are known to be highly expressed in the brain, while HCN4 channels are prevalent in the heart. The focus of this entry is the role that HCN channels serve in the brain.
HCN channels are thought to consist of four either indentical or non-identical subunits that are integrally embedded in the cell membrane to create an ion-conducting pore.  The ribbon model to the left depicts HCN1. HCN1 and HCN2 (not shown) are the two HCN channels found in the brain.
Function in the Brain
The pacemaker currents created by HCN channels are thought to regulate rhythmic or oscillatory activity in neurons within the brain. The flow of ions through the channel itself modulates neuron polarization and thus affects neuron excitability. Current research has revealed that HCN channels play an important role in the function of many areas of the brain, including the prefrontal cortex.
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.
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 vitro, 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.
- Luthi A, McCormick DA. 1998. Neuron. H-current: properties of a neuronal and network pacemaker. Vol. 21. pp 9-12.
- KChannelDB Potassium Channel entries
- Swiss-Prot entry
- 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.