KCNE1 tunes the sensitivity of KV7.1 to polyunsaturated fatty acids by moving turret residues close to the binding site

Abstract

The voltage-gated potassium channel K_V7.1 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_V7.1 via an electrostatic mechanism. The activating effect was abolished when K_V7.1 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_V7.1 restored PUFA effects on K_V7.1 co-expressed with KCNE1 in <i>Xenopus</i> oocytes. We propose that KCNE1 moves the S5-P-helix loop of K_V7.1 towards the PUFA-binding site, which indirectly causes PUFA protonation, thereby reducing the effect of PUFAs on K_V7.1. This mechanistic understanding of how KCNE1 alters K_V7.1 pharmacology is essential for development of drugs targeting the I_Ks channel.