Polyunsaturated Fatty Acid Analogues Act Anti-Arrhythmic on the Cardiac IKs Channel

Abstract

Polyunsaturated fatty acids (PUFAs) affect cardiac excitability. Kv7.1 and the β-subunit KCNE1 form the cardiac IKs channel that is central for cardiac repolarization. In this study, we explore the prospects of PUFAs as IKs channel modulators. We report that PUFAs open Kv7.1 via an electrostatic mechanism. Charged n-3 and n-6 PUFAs affect the voltage dependence of Kv7.1 by shifting the conductance versus voltage curve towards more negative voltages. In contrast, uncharged methyl esters of the PUFAs do not affect the voltage dependence of Kv7.1. Both the polyunsaturated acyl tail and the negatively charged carboxyl head group are required for PUFAs to open 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 thereby able to affect Kv7.1 channel voltage dependence. We further show that KCNE1 co-expression abolishes the PUFA effect on Kv7.1 by promoting PUFA protonation. PUFA analogues with a decreased pKa value, to preserve their negative charge at neutral pH, restore the sensitivity to open IKs channels. PUFA analogues with a positively charged head group inhibit IKs channels. These different PUFA analogues could be developed into drugs to treat cardiac arrhythmias. In support of this possibility, we show that a PUFA analogue with a permanently negatively charged head group acts anti-arrhythmic in cardiomyocytes. This permanently negatively charged PUFA analogue induces a shortening of action potential duration in embryonic rat cardiomyocytes and restores rhythmic beating in an arrhythmia model.