KCNE1 tunes the sensitivity of K _v 7.1 to polyunsaturated fatty acids by moving turret residues close to the binding site

The voltage-gated potassium channel K _V 7.1 and the auxiliary subunit KCNE1 together form the cardiac IKs channel, which is a proposed target for future anti-arrhythmic drugs. We previously showed that polyunsaturated fatty acids (PUFAs) activate K _V 7.1 via an electrostatic mechanism. The activating effect was abolished when K _V 7.1 was co-expressed with KCNE1, as KCNE1 renders PUFAs ineffective by promoting PUFA protonation. PUFA protonation reduces the potential of PUFAs as anti-arrhythmic compounds. It is unknown how KCNE1 promotes PUFA protonation. Here, we found that neutralization of negatively charged residues in the S5-P-helix loop of K _V 7.1 restored PUFA effects on K _V 7.1 co-expressed with KCNE1 in Xenopus oocytes. We propose that KCNE1 moves the S5-P-helix loop of K _V 7.1 towards the PUFA-binding site, which indirectly causes PUFA protonation, thereby reducing the effect of PUFAs on K _V 7.1. This mechanistic understanding of how KCNE1 alters K _V 7.1 pharmacology is essential for development of drugs targeting the IKs channel.