Delineation and functions of HCN channels in neurons

The observation of non-linear current-voltage relationships of membrane potential responses in neurons led to the discovery of hyperpolarization-induced membrane conductance. The main underlying hallmark of this conductance was the presence of sag - spontaneous depolarization of membrane potential during constant hyperpolarization in current-clamp mode. Gradually, the presence of underling hyperpolarization-activated cyclic nucleotide-gated non-selective cation channels (HCN, I_h, or I_f, where f is for funny) was established. The earliest delineation of HCN-mediated sag in the hippocampus was documented by Purpura, Prelevic, and Santini with a short communication in 1968. The study was performed using classical electrophysiology by impaling the perikaryon of hippocampal neurons, but the outcomes are as insightful as with the patch-clamp technique, and the quality of traces exceeds some of the recent recordings. However, the latter authors were not convinced that the sag phenomenon could play a role under physiological conditions. It is logical since a depolarization and linked excitability are frequently observed in vivo, but not a hyperpolarization. At least a sudden, sharp hyperpolarization does not occur in the CNS. Besides, in order to activate the HCN channels, the amplitude and duration of hyperpolarization should be significant and sufficient. Nonetheless, those with skepticism conveyed pioneer observations were pivotal, since the presence of sag - activation of HCN channels - may also play a role in autism and epilepsy.