Polyunsaturated Fatty Acids as Modulators of K_V7 Channels

Voltage-gated potassium channels of the K_V7 family are expressed in many tissues. The physiological importance of K_V7 channels is evident from specific forms of disorders linked to dysfunctional K_V7 channels, including variants of epilepsy, cardiac arrhythmia and hearing impairment. Thus, understanding how K_V7 channels are regulated in the body is of great interest. This Mini Review focuses on the effects of polyunsaturated fatty acids (PUFAs) on K_V7 channel activity and possible underlying mechanisms of action. By summarizing reported effects of PUFAs on K_V7 channels and native K_V7-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_V7 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_V7.1. 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_V7.1. Indirect effects include those mediated by PUFA metabolites. Indirect inhibitory effects involve K_V7 channel degradation and re-distribution from lipid rafts. Understanding how PUFAs regulate K_V7 channels may provide insight into physiological regulation of K_V7 channels and bring forth new therapeutic strategies.