Advances in Understanding of Structure, Function and Plasticity of HCN Channels

Hyperpolarization-activated, cyclic nucleotide-sensitive, cation non-selective (HCN) channels are gaining attention in recent years. These ion-channels are gated by two factors: voltage, specifically hyperpolarization and some subunits, more than others, by cyclic nucleotides. They conduct both sodium and potassium ions, and regulate many functions in both neuronal and non-neuronal cells. In neurons, HCN channel functions range from setting resting potential, synaptic normalization, gain control, after-hyperpolarization, setting responses in dendrites, mediating cannabinoid role in neuronal plasticity to the gating of plasticity. Emerging properties of circuits expressing HCN channels manifest in the form of various kinds of functions like brain rhythms, perception, spatial learning, executive memory, epilepsy, ataxia, depression, sound localization, anxiety, etc. We are beginning to understand the roles of these channels in non-neuronal cells and we would discover more such roles in the future. Following ischaemia, there is HCN over-expression in the reactive astrocytes. There is an altered expression of HCN channels in few tissues in diabetic animal models. Recent evidence suggests that HCN channels are also involved in uterine contractions and renal functioning. This review focuses on the function, structure, interacting proteins and developmental plasticity that enable the versatility of HCN channels.