Polyunsaturated Fatty acids as Kv7 Channel Modulators

Abstract

Lipids in different forms can directly affect the electric activity of excitable tissues, in some cases via direct interactions with ion channels. For instance is the activity of Kv7 (KCNQ) channels dependent on the abundance of the phospholipid PIP2 in the inner leaflet of the plasma membrane. In this work we instead studied the effect of free extracellular polyunsaturated fatty acids (PUFAs) on Kv7 channels expressed in Xenopus oocytes. We show that ω-3 and ω-6 PUFAs affected the voltage dependence of Kv7.1 and Kv7.2/3 by shifting the conductance versus voltage (G(V)) curves in negative direction along the voltage axis. The effect was pH dependent. In contrast, uncharged methyl esters of the PUFAs did not affect the voltage dependences. Fatty acid requirements and PUFA-induced effects were similar to those previously reported for the Shaker K channel suggesting a similar modulatory mechanism of action, i.e. our previously proposed lipoelectric mechanism in which PUFAs electrostatically affect channel opening. The putative PUFA interaction site is close to the positioning of auxiliary KCNE subunits. We therefore also investigated the impact of KCNE subunits and found that PUFA potency was influenced by KCNE association. Kv7.1 and Kv7.2/3 channels are important for cardiac and neuronal excitability, respectively, and mutated channels resulting in loss-of-function cause heart arrhythmias and epilepsy. The PUFA-induced opening of Kv7 channels found in this study may therefore help explain the antiexcitable properties of PUFAs and the fat-rich ketogenic diet. Lipoelectric modification of the channels voltage dependence could be a future new approach for pharmacological treatment.