Differential Sensitivity of Cardiac Ion Channels to Polyunsaturated Fatty Acid Analogues

Ion channels are important regulators of cellular excitability in tissues such as the heart and brain. In the heart, the ventricular action potential depends on the activity of several different ion channels including Na+ channels, Ca2+ channels, and K+ channels. When any of these currents are disrupted by mutation, patients can develop Long QT Syndrome (LQTS). LQTS predisposes the individual to ventricular fibrillation that can lead to sudden cardiac death. Polyunsaturated fatty acids (PUFAs) have emerged as therapeutic candidates for LQTS because they are known to modulate the activity of different ion channels. We have demonstrated that PUFAs can regulate the activity of the cardiac IKs channel (Kv7.1/KCNE1), by shifting the voltage-dependence of the channel to more negative voltages. It is not known, however, whether PUFAs influence specific ion channels or whether the PUFAs nonspecifically modify multiple ion channels in the heart. To understand the selectivity of different PUFAs, we applied PUFAs and modified PUFAs to the cardiac Nav1.5 channel, the Cav1.2 channel, and the IKs channel. Here we demonstrate that PUFA analogues range from highly specific for single ion channels to nonspecifically activating all three cardiac ion channels (Nav1.5, Cav1.2, and IKs). We have found that PUFAs containing a glycine head group have specific effects on IKs channels, whereas PUFAs with a taurine head group are more selective for Nav1.5 and Cav1.2 channels. Our data suggest that modified PUFAs could be tailored towards specific forms of LQTS based on the channel carrying the disease causing mutation.