HCN channels consist of four subunits, HCN1-4, that can assemble in various combinations and conformations. These channels are expressed in brain, heart, and retina. HCN1 is the common isoform present in hippocampus, neocortex, and cerebellar cortex. HCN2 expression is seen in midbrain and thalamus, while HCN4 is the predominant isoform in heart, thalamic nuclei, basal ganglia, and olfactory bulb.
Furthermore, HCN channels show distinct subcellular locations and distinct physiology when they are expressed in dendrites vs cell somas. HCN channels regulate neuronal firing and excitability via the hyperpolarization-activated current Ih (also called h-current). HCN channels are activated by hyperpolarized states and are constitutively active at rest. This allows HCN channels to modulate neuronal excitability by stabilizing the membrane potential against both excitatory and inhibitory inputs. Altered expression or activity of HCN channels can lead to excessive hyperactivity such as seen in epilepsy patients. Thus, HCN channels provide a potential target to stabilize pathological neuronal hyperactivity.
