Fatty acid analogue N-arachidonoyl taurine restores function of I(Ks) channels with diverse long QT mutations

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. DOI: http://dx.doi.org/10.7554/eLife.20272.001