Polyunsaturated Fatty Acids as Modulators of K(V)7 Channels

Voltage-gated potassium channels of the K(V)7 family are expressed in many tissues. The physiological importance of K(V)7 channels is evident from specific forms of disorders linked to dysfunctional K(V)7 channels, including variants of epilepsy, cardiac arrhythmia and hearing impairment. Thus, understanding how K(V)7 channels are regulated in the body is of great interest. This Mini Review focuses on the effects of polyunsaturated fatty acids (PUFAs) on K(V)7 channel activity and possible underlying mechanisms of action. By summarizing reported effects of PUFAs on K(V)7 channels and native K(V)7-mediated currents, we conclude that the generally observed effect is a PUFA-induced increase in current amplitude. The increase in current is commonly associated with a shift in the voltage-dependence of channel opening and in some cases with increased maximum conductance. Auxiliary KCNE subunits, which associate with K(V)7 channels in certain tissues, may influence PUFA effects, though findings are conflicting. Both direct and indirect activating PUFA effects have been described, direct effects having been most extensively studied on K(V)7.1. The negative charge of the PUFA head-group has been identified as critical for electrostatic interaction with conserved positively charged amino acids in transmembrane segments 4 and 6. Additionally, the localization of double bonds in the PUFA tail tunes the apparent affinity of PUFAs to K(V)7.1. Indirect effects include those mediated by PUFA metabolites. Indirect inhibitory effects involve K(V)7 channel degradation and re-distribution from lipid rafts. Understanding how PUFAs regulate K(V)7 channels may provide insight into physiological regulation of K(V)7 channels and bring forth new therapeutic strategies. Funding Agencies|European Research Council (ERC) under the European Unions Horizon 2020 research and innovation programEuropean Research Council (ERC) [850622]