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.
Highlights
The voltage-gated potassium channel KV7.1 and the auxiliary subunit KCNE1 together form the slowly activating and voltage-gated IKs potassium channel, an important channel for cardiomyocyte repolarization (Nerbonne and Kass, 2005)
We examined how KCNE1 changes the pharmacology of KV7.1 by inducing polyunsaturated fatty acids (PUFAs) protonation
Our results show that negatively charged residues in the loop connecting S5 to the pore helix, but not charged residues in the extracellular part of KCNE1, are important for KCNE1-induced docosahexaenoic acid (DHA) protonation
Summary
The voltage-gated potassium channel KV7.1 and the auxiliary subunit KCNE1 together form the slowly activating and voltage-gated IKs potassium channel, an important channel for cardiomyocyte repolarization (Nerbonne and Kass, 2005). We showed that the inhibiting effect of the positively charged PUFA analogue arachidonoyl amine (AA+) was potentiated by KCNE1, as if the decreased local pH at the PUFAbinding site further protonated the amine head of AA+ (Liin et al, 2015b). This improved protonation improves the electrostatic repulsion on the voltage sensor induced by AA+ (Liin et al, 2015b). We propose a model in which KCNE1 indirectly modulates the pharmacology of KV7.1 by inducing structural rearrangements of the extracellular S5-P-helix loop of KV7.1, moving acidic residues in this loop close to the DHA molecule
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