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

ELife
Johan E LarssonSara I Liin

Abstract

The voltage-gated potassium channel KV7.1 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 KV7.1 via an electrostatic mechanism. The activating effect was abolished when KV7.1 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 KV7.1 restored PUFA effects on KV7.1 co-expressed with KCNE1 in Xenopus oocytes. We propose that KCNE1 moves the S5-P-helix loop of KV7.1 towards the PUFA-binding site, which indirectly causes PUFA protonation, thereby reducing the effect of PUFAs on KV7.1. This mechanistic understanding of how KCNE1 alters KV7.1 pharmacology is essential for development of drugs targeting the IKs channel.

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Citations

Dec 23, 2019·The Journal of General Physiology·Briana M BohannonH Peter Larsson
Jul 1, 2020·Frontiers in Physiology·Johan E LarssonSara I Liin
Jun 26, 2020·Frontiers in Physiology·Yundi WangDavid Fedida
Dec 12, 2019·Biochimica Et Biophysica Acta. Biomembranes·Gunjan DixitGary A Lorigan
Apr 17, 2021·Trends in Pharmacological Sciences·Shira Burg, Bernard Attali
May 4, 2021·The Journal of General Physiology·Samira YazdiSara I Liin
Oct 27, 2021·The Journal of General Physiology·Marina AngeliniRiccardo Olcese

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