Fatty acid analogue N-arachidonoyl taurine restores function of IKschannels with diverse long QT mutations.
About 300 loss-of-function mutations in the IKschannel 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 IKschannel activators for treatment of these arrhythmias. We find that several Long QT syndrome-associated IKschannel mutations shift channel voltage dependence and accelerate channel closing. Voltage-clamp fluorometry experiments and kinetic modeling suggest that similar mutation-induced alterations in IKschannel 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 IKschannel and affect the channel by different molecular mechanisms. N-arachidonoyl taurine is therefore an interesting prototype compound that may inspire development of future IKschannel activators to treat Long QT syndrome caused by diverse IKschannel mutations.
Department of Physiology and Biophysics, University of Miami, Miami, United States.|Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Sara I
0000-0001-8493-0114
SI
Liin
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Johan E
JE
Larsson
Department of Physiology and Biophysics, University of Miami, Miami, United States.
Rene
R
Barro-Soria
The Danish Arrhythmia Research Centre, University of Copenhagen, Copenhagen, Denmark.|Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Bo Hjorth
BH
Bentzen
Department of Physiology and Biophysics, University of Miami, Miami, United States.
H Peter
HP
Larsson
D001095:Arachidonic Acids / Q000378:metabolism*; D005470:Fluorometry; D006801:Humans; D007700:Kinetics; D008133:Long QT Syndrome / Q000235:genetics*; D009154:Mutation; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics* / Q000378:metabolism*; D013654:Taurine / Q000031:analogs & derivatives* / Q000378:metabolism
D001095:Arachidonic Acids; D024642:Potassium Channels, Voltage-Gated; C529118:arachidonoyltaurine; D013654:Taurine
KCNE1; KCNQ1; Kv7.1; antiarrhythmic; biophysics; polyunsaturated fatty acid; structural biology; xenopus
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