Cardiac and neuronal HCN channelopathies

Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are expressed as four different isoforms (HCN1-4) in the heart and in the central and peripheral nervous systems. In the voltage range of activation, HCN channels carry an inward current mediated by Na+ and K+, termed If in the heart and Ih in neurons. Altered function of HCN channels, mainly HCN4, is associated with sinus node dysfunction and other arrhythmias such as atrial fibrillation, ventricular tachycardia, and atrioventricular block. In recent years, several data have also shown that dysfunctional HCN channels, in particular HCN1, but also HCN2 and HCN4, can play a pathogenic role in epilepsy; these include experimental data from animal models, and data collected over genetic mutations of the channels identified and characterized in epileptic patients. In the central nervous system, alteration of the Ih current could predispose to the development of neurodegenerative diseases such as Parkinson’s disease; since HCN channels are widely expressed in the peripheral nervous system, their dysfunctional behavior could also be associated with the pathogenesis of neuropathic pain. Given the fundamental role played by the HCN channels in the regulation of the discharge activity of cardiac and neuronal cells, the modulation of their function for therapeutic purposes is under study since it could be useful in various pathological conditions. Here we review the present knowledge of the HCN-related channelopathies in cardiac and neurological diseases, including clinical, genetic, therapeutic, and physiopathological aspects.