Fatty acid analogue N-arachidonoyl taurine restores function of IKs channels with diverse long QT mutations

Abstract

About 300 loss-of-function mutations in the I_Ks channel have been identified in patients with Long QT syndrome and cardiac arrhythmia. How specific mutations cause arrhythmia is largely unknown and there are no approved I_Ks channel activators for treatment of these arrhythmias. We find that several Long QT syndrome-associated I_Ks channel mutations shift channel voltage dependence and accelerate channel closing. Voltage-clamp fluorometry experiments and kinetic modeling suggest that similar mutation-induced alterations in I_Ks channel currents may be caused by different molecular mechanisms. Finally, we find that the fatty acid analogue N-arachidonoyl taurine restores channel gating of many different mutant channels, even though the mutations are in different domains of the I_Ks channel and affect the channel by different molecular mechanisms. N-arachidonoyl taurine is therefore an interesting prototype compound that may inspire development of future I_Ks channel activators to treat Long QT syndrome caused by diverse I_Ks channel mutations.