Effect of the Membrane Environment on Pharmacologic Inhibition of hERG K⁺ Channel Activity

hERG encodes K_V11.1 voltage-gated K⁺ channels, which generate the rapidly activating delayed rectifier K⁺ current that contributes to repolarization of the cardiac action potential. In addition to being targeted by many class III antiarrhythmic agents, these channels are also inhibited by a multitude of other pharmacological compounds, which can produce acquired long QT syndrome, leading to polymorphic ventricular tachycardia. While most drugs are thought to interact with a hydrophilic binding site in the channel pore, it has been postulated that some compounds act by perturbing the membrane environment or acting at hydrophobic sites accessed through the plasma membrane.

Because hERG channels reside in cholesterol rich lipid raft domains, we hypothesized that disrupting the membrane environment by depleting cholesterol might alter inhibition of channel activity by certain drugs.

We tested our hypothesis by examining the effect that depleting membrane cholesterol with methyl-β-cyclodextrin has on the ability of several compounds to inhibit hERG channels expressed in HEK293 cells.

We found that cholesterol depletion significantly increased the sensitivity of the whole cell current to inhibition by ibutilide, while decreasing the currents sensitivity to dofetilide and amiodarone at negative membrane potentials.

These results support the idea that the lipid environment of the plasma membrane plays a role in the ability of certain drugs to inhibit hERG channel activity. Differences in membrane cholesterol content may affect the ability of some hERG channel blockers to produce arrhythmogenic behavior.