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

Johan E. Larsson, H. Peter Larsson, Sara I. Liin

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere37257
JournaleLife
Volume7
DOIs
StatePublished - Jul 17 2018

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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