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 I(Ks) 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 I(Ks) channel.