N-Arachidonoyl Taurine Rescues Diverse Long QT Syndrome-Associated Mutations in the Cardiac I←Ks Channel

The cardiac I←Ks channel is important for cardiomyocyte repolarization. More than 300 loss-of-function mutations in the genes encoding I←Ks have been identified in patients with Long QT syndrome. These mutations cause cardiac arrhythmias, such as torsades de pointes and ventricular fibrillation. How specific mutations cause arrhythmia is, however, not known in most cases and there is no approved I←Ks channel activator for treatment of arrhythmia. In this work, we study the biophysical properties and mechanism of loss of function of Long QT syndrome-associated I←Ks channel mutations expressed in Xenopus laevis oocytes. We next test the ability of the fatty acid analogue N-arachidonoyl taurine to restore the function of these mutants. Using two-electrode voltage clamp, we find that a number of Long QT syndrome-associated, loss-of-function I←Ks channel mutations shift the voltage dependence of opening towards positive voltages and speed up channel closing. Using voltage clamp fluorometry, we show that these alterations are caused by either disrupted voltage sensor movement or gate opening. We also find that the fatty acid analogue N-arachidonoyl taurine activates all tested Long QT syndrome-associated I←Ks channel mutations by shifting their voltage dependence of activation towards more negative voltages and altering the kinetics of channel opening and closing. Thus, N-arachidonoyl taurine restores the function of these mutants and compensates for the loss of function induced by these mutations, whether the mutations disrupted voltage sensor movement or gate opening. N-AT also shortens a drug-induced prolonged QT interval in isolated perfused guinea pig hearts in Langendorff preparation back to a normal range. N-AT is therefore a promising future I←Ks channel activator that may restore a physiological QT interval by enhancing the function of diverse Long QT syndrome I←Ks mutants, independent of the mutational defect.