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

• Published in: eLife 2018-07, Vol.7
• Main Authors: Larsson, Johan E, Larsson, H Peter, Liin, Sara I
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Cells, Cultured; Fatty Acids, Unsaturated - metabolism; KCNQ1 Potassium Channel - genetics; KCNQ1 Potassium Channel - metabolism; Models, Molecular; Oocytes - enzymology; Oocytes - metabolism; Potassium Channels, Voltage-Gated - genetics; Potassium Channels, Voltage-Gated - metabolism; Protein Conformation; Xenopus
• ISSN: 2050-084X
• DOI: 10.7554/eLife.37257

The voltage-gated potassium channel K 7.1 and the auxiliary subunit KCNE1 together form the cardiac I channel, which is a proposed target for future anti-arrhythmic drugs. We previously showed that polyunsaturated fatty acids (PUFAs) activate K 7.1 via an electrostatic mechanism. The activating effect was abolished when K 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 7.1 restored PUFA effects on K 7.1 co-expressed with KCNE1 in oocytes. We propose that KCNE1 moves the S5-P-helix loop of K 7.1 towards the PUFA-binding site, which indirectly causes PUFA protonation, thereby reducing the effect of PUFAs on K 7.1. This mechanistic understanding of how KCNE1 alters K 7.1 pharmacology is essential for development of drugs targeting the I channel.