Fatty acid analogue N-arachidonoyl taurine restores function of IKs channels with diverse long QT mutations.

Sara I Liin,Rene Barro-Soria,Johan E Larsson,H Peter Larsson,Bo Hjorth Bentzen

doi:10.7554/elife.20272

Sara I Liin, Rene Barro-Soria + Show 3 more

Open Access

https://doi.org/10.7554/elife.20272

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Abstract

About 300 loss-of-function mutations in the IKs channel have been identified in patients with Long QT syndrome and cardiac arrhythmia. How specific mutations cause arrhythmia is largely unknown and there are no approved IKs channel activators for treatment of these arrhythmias. We find that several Long QT syndrome-associated IKs channel mutations shift channel voltage dependence and accelerate channel closing. Voltage-clamp fluorometry experiments and kinetic modeling suggest that similar mutation-induced alterations in IKs channel currents may be caused by different molecular mechanisms. Finally, we find that the fatty acid analogue N-arachidonoyl taurine restores channel gating of many different mutant channels, even though the mutations are in different domains of the IKs channel and affect the channel by different molecular mechanisms. N-arachidonoyl taurine is therefore an interesting prototype compound that may inspire development of future IKs channel activators to treat Long QT syndrome caused by diverse IKs channel mutations.

Highlights

Long QT syndrome (LQTS) is a condition of the heart which in most cases is caused by a mutation in cardiac ion channels (Hedley et al, 2009; Morita et al, 2008)
Our voltage-clamp fluorometry experiments together with kinetic modeling are compatible with a model in which the S225L mutation primarily interferes with the main S4 movement, whereas the F351A mutation interferes with later gating transitions associated with pore opening
We show that all studied LQTS and LQTS-like mutations i) shift the G(V) of KV7.1+KCNE1 towards more positive voltages, and/or ii) accelerate KV7.1+KCNE1 closing

Summary

Introduction

Long QT syndrome (LQTS) is a condition of the heart which in most cases is caused by a mutation in cardiac ion channels (Hedley et al, 2009; Morita et al, 2008). About 300 different mutations in the IKs channel have been shown to cause abnormal heart rhythms in individuals with a disorder called long QT syndrome People with this condition may suddenly black out because their heart develops prolonged electric waves that prevent blood from being pumped properly. Potential mechanisms for KV7.1+KCNE1 channel loss of function by a mutation could, for example, be interference with voltage sensor movement, gate opening, or membrane expression. We investigate the biophysical properties and potential mechanism of action of LQTS-associated KV7.1+KCNE1 channel mutations and test the ability of the fatty acid analogue N-arachidonoyl taurine (N-AT) to restore the function of these mutants. Comparison of current amplitude of wild-type KV7.1+KCNE1 and LQTS and LQTS-like mutants when expressed in Xenopus oocytes. This suggests that N-AT may function as a general activator of KV7.1+KCNE1 channels with diverse mutational defects

Results

Discussion

Materials and methods

Funding Funder National Institutes of Health