Pathophysiology of HCN channels

Abstract

Hyperpolarization-activated cation currents termed I (f/h) are observed in many neurons and cardiac cells. Four genes (HCN1-4) encode the channels underlying these currents. New insights into the pathophysiological significance of HCN channels have been gained recently from analyses of mice engineered to be deficient in HCN genes. Lack of individual subunits results in markedly different phenotypes. Disruption of HCN1 impairs motor learning but enhances spatial learning and memory. Deletion of HCN2 results in absence epilepsy, ataxia, and sinus node dysfunction. Mice lacking HCN4 die during embryonic development and develop no sinoatrial node-like action potentials. In the present review, we summarize the physiology and pathophysiology of HCN channel family members based primarily on information from the transgenic mouse models and on data from human patients carrying defects in HCN4 channels.

PIP2-Mediated HCN3 Channel Gating Is Crucial for Rhythmic Burst Firing in Thalamic Intergeniculate Leaflet Neurons

“…For example, HCN1 regulates motor learning and spatial memory (Nolan et al, 2003(Nolan et al, , 2004, while HCN2 regulates thalamic excitability associated with absence seizures Ying et al, 2007b). The function of brain HCN3, however, has remained elusive (Herrmann et al, 2007). HCN channel gating is controlled by both ligand and voltage Biel et al, 2009).…”

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

“…HCN1 promotes the ability to learn new motor tasks, but it inhibits spatial learning and memory 30 . HCN2 plays an important role in the regulation of cellular excitability, motion control and synus node functioning because its knockout results in absence epilepsy, ataxia and sinus node dysfunction 31 . HCN4 is vital for cardiac development; its knockout fails to have sinoatrial node-like action potential in mice and such knockouts are embryonic lethal [31][32][33] .…”

“…Recently, the role of HCN channels in depression is also coming to the fore 36,81 . Reduction of HCN channels in thalamus and cortex (through TRIP8b knockout) results in a model of absence epilepsy 82 and recent work has shown these channels to be a good drugable targets for epilepsy treatment 31,83,84 . Auditory roles of these channels are also becoming clearer with new information, with the latest study showing their crucial role in tinnitus too 85 .…”

Expression of hyperpolarization-activated cyclic nucleotide-gated channel isoforms in a canine model of atrial fibrillation

“…Changes to a number of ion channel currents may result in electrical remodeling, including the L-type calcium current, the transient outward potassium current when downregulated and the inward rectifier potassium current when upregulated (6). Previous studies have found that the hyperpolarization current (I f ) is associated with atrial electrical remodeling in patients with AF (7)(8)(9).…”

“…The molecular propagators of the I f current are hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (11). Therefore, the inhibition of HCN channels has become a focus of study for the treatment of arrhythmia (6). However, few studies have investigated changes in the expression of HCN channel isoforms in atrial cells following AF.…”