| Scientific Background: | Hyperpolarization-activated cation currents (Ih) appear in the heart and the brain and play a crucial role in controlling electrical pacemaker activity, contributing to biological processes such as heartbeat, sleep-wake cycle and synaptic plasticity. The Ih currents are generated by the Hyperpolarization-activated Cyclic Nucleotide-gated channel family (HCN), which comprises four homologous members, HCN1-4. Each HCN subunit consists of six transmembrane (TM) domains, a pore region between TM5-TM6 and a cyclic nucleotide binding domain in the cytoplasmic C-terminus. The HCN subunits can form functional homomers and can also co-assemble into functional heteromers. The channels are closely related to each other and are about 60% homologous. However, they differ from each other in their cytoplasmic N- and the C-termini. HCN1-4 differ in their speed of activation and the extent to which they are modulated by cAMP. HCN1 is the fastest channel, followed by HCN2, HCN3 and HCN4. This family of channels has been implicated in an alternative mechanism for chronic pain. |
