Fiore Chase M, Quigley Kate, Vorobyov Igor, Clancy Colleen E, Harvey Robert D
Department of Pharmacology, University of Nevada, Reno, Reno, Nevada, USA.
Department of Physiology and Membrane Biology, University of California-Davis, Davis, California, USA.
JACC Clin Electrophysiol. 2025 Apr;11(4):708-719. doi: 10.1016/j.jacep.2024.11.016. Epub 2025 Jan 29.
hERG encodes K11.1 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.
hERG编码K11.1电压门控钾通道，该通道产生快速激活的延迟整流钾电流，有助于心脏动作电位的复极化。除了被许多III类抗心律失常药物作用外，这些通道还受到多种其他药理化合物的抑制，这些化合物可导致获得性长QT综合征，进而引发多形性室性心动过速。虽然大多数药物被认为与通道孔中的亲水性结合位点相互作用，但据推测，一些化合物是通过扰乱膜环境或作用于通过质膜进入的疏水性位点而起作用的。
由于hERG通道存在于富含胆固醇的脂筏结构域中，我们推测通过消耗胆固醇来破坏膜环境可能会改变某些药物对通道活性的抑制作用。
我们通过检测用甲基-β-环糊精消耗膜胆固醇对几种化合物抑制HEK293细胞中表达的hERG通道能力的影响来验证我们的假设。
我们发现胆固醇消耗显著增加了全细胞电流对伊布利特抑制的敏感性，同时在负膜电位下降低了对多非利特和胺碘酮的电流敏感性。
这些结果支持质膜的脂质环境在某些药物抑制hERG通道活性的能力中起作用这一观点。膜胆固醇含量的差异可能会影响一些hERG通道阻滞剂产生致心律失常行为的能力。
