The effects of polyunsaturated fatty acids on the cardiac IKR channel.

Abstract

The cardiac action potential is primarily generated by sodium and calcium channels, which depolarize the membrane potential, and by potassium channels that repolarize the membrane potential and terminate the action potential. Mutations in potassium channels Kv11.1 (also called hERG) and Kv7.1/KCNE1 (also called KCNQ1/KCNE1), which generate the IKr and IKs currents, respectively, are the most common cause of congenital defects that lead to Long QT Syndrome (LQTS). LQTS is an arrhythmia disorder that predisposes individuals to ventricular fibrillation and sudden cardiac death and is characterized by a delayed repolarization phase and a prolonged QT interval. Some PUFA (Polyunsaturated Fatty Acid) analogs have been shown to be IKs activators that have the potential to reduce the QT interval and lessen risks associated with LQTS. However, the broad modulating effects of different PUFA analogs on all three cardiac ion channel families (NaV, CaV, and Kv) make it necessary for promising analogs to be channel specific to avoid off- target effects. So far the effects of PUFA analogs on hERG channels remain unknown. To determine how the application of PUFA analogs modifies the hERG channel we use the Two-Electrode Voltage Clamp (TEVC) electrophysiology method to record whole cell channel activity from Xenopus oocytes expressing the hERG channel. Here we evaluate both Gmax and V0.5, as well as the rate of activation, inactivation and recovery from inactivation, as measurements of the PUFA analog effects on channel activity. It is important to rule out hERG modulation by PUFA analogs to fill this gap in our understanding of the PUFA pharmacophore that currently limits our ability to design channel-specific PUFA compounds.