Cholesterol modulation exerted isoform-specific effects on human HCN channels, including a +10 mV depolarizing shift in HCN4 activation upon depletion and altered mode-shifting in HCN2 and HCN4.
Does cholesterol modulation alter the electrophysiological properties and trafficking of human HCN1, HCN2, and HCN4 channels in vitro?
Cholesterol modulates human HCN channel gating, mode-shifting, and trafficking in an isoform-specific manner, providing a potential mechanism for arrhythmias associated with altered cholesterol levels.
Cholesterol has been shown to regulate numerous ion channels. HCN channels represent the molecular correlate of If or Ih in sinoatrial node (SAN) and neuronal cells. Previous studies have implicated a role for cholesterol in the regulation of rabbit HCN4 channels with effects on pacing in the rabbit SAN. Using electrophysiological and biochemical approaches, we examined the effect of cholesterol modulation on human HCN1, HCN2 and HCN4 isoforms. Patch-clamp experiments uncovered isoform specific differences in the effect of cholesterol on gating kinetics upon depletion by MβCD or mevastatin or enrichment using MβCD/cholesterol. Most dramatically cholesterol had isoform specific effects on mode-shifting, which has been suggested to play a key role in stabilizing firing rate and preventing arrhythmic firing in SAN cells and neurons. Mode-shifting in HCN1 channels was insensitive to cholesterol manipulation, while HCN2 and HCN4 were strongly affected. Trafficking of each isoform to the plasma membrane was also affected by cholesterol modulation differentially between isoforms, however, each isoform remained localized in lipid raft domains after cholesterol depletion. These effects may contribute to the side effects of cholesterol reducing therapies including disrupted heart rhythm and neuropathic pain, as well as the susceptibility of sinus dysfunction in patients with elevated cholesterol.
Fürst et al. (Fri,) reported a other. Cholesterol modulation (depletion or enrichment) vs. Untreated control cells was evaluated on HCN channel electrophysiological properties (activation, deactivation, and hysteresis). Cholesterol modulation exerted isoform-specific effects on human HCN channels, including a +10 mV depolarizing shift in HCN4 activation upon depletion and altered mode-shifting in HCN2 and HCN4.