KCNE1 Modulates the Sensitivity of Kv7.1 to Polyunsaturated Fatty Acids

Abstract

Polyunsaturated fatty acids (PUFAs) affect cardiac excitability by interacting with ion channels. In this work we studied the effect of PUFAs on cardiac Kv7.1 channels. We show that charged n-3 and n-6 PUFAs affect the voltage dependence of Kv7.1 by shifting the conductance versus voltage (G(V)) curve towards hyperpolarized voltages. In contrast, uncharged methyl esters of the PUFAs do not affect the voltage dependence of Kv7.1. The PUFA effect is pH dependent. This is likely because high pH deprotonates the PUFA, making a larger fraction of PUFA molecules negatively charged and able to affect Kv7.1 channel voltage dependence. The structural requirement of PUFAs to induce Kv7.1 channel opening and the PUFA-induced effect on channel voltage dependence were similar to those previously reported for the Shaker K channel. This suggests a general modulatory mechanism in which PUFAs electrostatically interact with the voltage-sensor domain of the channel to induce channel opening. The putative PUFA interaction site on Kv7.1, homologous to the previously reported PUFA interaction site on the Shaker K channel, is close to the position of the auxiliary KCNE1 subunit in the cardiac IKs channel. We therefore also investigated the impact of KCNE1 on PUFA potency and found that the PUFA effect on Kv7.1 was decreased by KCNE1 coexpression. By investigating the mechanism for KCNE1-induced reduction of channel sensitivity to PUFAs, we found that KCNE1 protonates the PUFA molecule making PUFAs uncharged and ineffective. We furthermore explored the possibility to circumvent KCNE1-effects on PUFA potency by testing PUFA analogues with different properties. This study provides mechanistic information on how KCNE1 affects pharmacological sensitivity of the Kv7.1 channel. This study may also form the basis for the development of future Kv7.1 channel openers to be used in the treatment of cardiac arrhythmia.