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Structure

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.

HCN channels are regulated by both intracellular and extracellular molecules, but most importantly, cyclic nucleotides (cAMP, cGMP, cCMP). Binding of cyclic nucleotides lowers the voltage potential of HCN channels, thus activating them. cAMP is a primary agonist of HCN2 while cGMP and cCMP may also bind. Research has shown, however, that all three are potent agonists.

HCN channels 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 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. HCN channels have been shown to be important for activity-dependent mechanisms for olfactory sensory neuron growth.

HCN1 and 2 channels have been found in dorsal root ganglia, basal ganglia, and the dendrites of neurons in the hippocampus. HCN channel trafficking along dendrites in the hippocampus of rats has shown that HCN channels are quickly shuttled to the surface in response to neural activity. HCN channels have also been observed in the retrotrapezoid nucleus (RTN), a respiratory control center that responds to chemical signals such as CO₂. When HCN is inhibited, serotonin fails to stimulate chemoreceptors in the RTN, thus increasing respiratory activity. This illustrates a connection between HCN channels and respiratory regulation. Due to the complex nature of HCN channel regulation, as well as the complex interactions between multiple ion channels, HCN channels are fine-tuned to respond to certain thresholds and agonists. This complexity is believed to affect neural plasticity.

HCN channels 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 through HCN channels, called the funny current or pacemaker current (I_f), plays a key role in the generation and modulation of cardiac rhythmicity, as they are responsible for the spontaneous depolarization in pacemaker action potentials in the heart. HCN4 isoforms are regulated by cCMP and cAMP and these agonists have been shown to affect I_f.