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Fatty acid analogue N-arachidonoyl taurine restores function of I-Ks channels with diverse long QT mutations
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of Miami, FL, USA.ORCID iD: 0000-0001-8493-0114
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0003-3852-1015
University of Miami, FL, USA.
The Danish Arrhythmia Research Centre, University of Copenhagen, Copenhagen, Denmark; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
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2016 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e20272Article in journal (Refereed) Published
Abstract [en]

About 300 loss-of-function mutations in the I-Ks 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 I-Ks 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.

Place, publisher, year, edition, pages
ELIFE SCIENCES PUBLICATIONS LTD , 2016. Vol. 5, article id e20272
National Category
Biophysics
Identifiers
URN: urn:nbn:se:liu:diva-133008DOI: 10.7554/eLife.20272ISI: 000387142300001PubMedID: 27690226OAI: oai:DiVA.org:liu-133008DiVA, id: diva2:1054673
Note

Funding Agencies|National Institutes of Health [R01GM109762]; American Heart Association [16GRNT30990060]; Svenska Sallskapet for Medicinsk Forskning; Vetenskapsradet [524-2011-6806]; Northwest Lions Foundation

Available from: 2016-12-08 Created: 2016-12-07 Last updated: 2020-05-12Bibliographically approved
In thesis
1. Molecular mechanisms of modulation of KV7 channels by polyunsaturated fatty acids and their analogues
Open this publication in new window or tab >>Molecular mechanisms of modulation of KV7 channels by polyunsaturated fatty acids and their analogues
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Ion channels are membrane proteins that regulate the permeability of ions across the cell membrane. The sequential opening of different types of ion channels produces action potentials in excitable cells. Action potentials are a way for the body to, for example, transmit signals quickly over a long distance.

The KV7 family is an important group of voltage-gated potassium channels. Mutations that cause dysfunction in members of the KV7 family are associated with several forms of disease. Compounds that can activate KV7 channels have previously been shown to work as medical treatments. However, the previously available antiepileptic drug retigabine, has been withdrawn due to adverse effects. Thus, there is a need for further development of compounds that target these channels. PUFA and PUFA analogs have previously been demonstrated to activate KV7.1 through an electrostatic mechanism. This thesis investigates new aspects of the interaction between KV7 channels and PUFA-related compounds.

The data in this thesis are from human KV7 channels expressed in Xenopus laevis oocytes. The currents produced by the channels expressed in the oocytes have been studied using twoelectrode voltage clamp. Our aim was to study the mechanism for the activation of KV7 channels by PUFA and PUFA analogs. More specifically, we intended to study why the beta subunit KCNE1 abolishes the activating effect of PUFA on KV7.1 and how PUFAs activate KV7.2 and KV7.3. Additionally, we wanted to study aspects that may affect whether these compounds are viable as medical treatments. For instance, whether these compounds can activate channels containing disease-causing mutations and whether we can improve compound selectivity towards certain KV7 channels.

In Paper I, we introduce disease-causing mutations found in patients into KV7.1 and KCNE1. The characterization showed that these channels had altered biophysical properties compared to wild type channels. A PUFA analog was found to activate and, to a large degree, restore wild type-like biophysical properties in the mutated channels regardless of the localization of the mutation in the channel.

In Paper II, we demonstrate why PUFA is unable to activate KV7.1 co-expressed with beta subunit KCNE1. KCNE1 induces a conformational change of KV7.1 that moves the S5-Phelix loop closer to the PUFA binding site. This causes negative charges of the loop to attract protons that reduce local pH at the PUFA binding site. The decreased local pH leads to protonation of PUFA and the PUFAs therefore lose their negative charge. Thus, PUFA cannot activate KV7.1 when it is co-expressed with KCNE1.

In Paper III, we study a group of PUFA-related substances, endocannabinoids, on KV7 channels. One endocannabinoid, Arachidonoyl-L-Serine (ARA-S), was identified as a potent activator of the neuronal M-channel, comprising KV7.2 and KV7.3 heteromers. We study the activating mechanism of ARA-S in KV7.2 and KV7.3, demonstrating how the activating effect is linked to two parts of the channel protein, one in the voltage sensor domain and the other in the pore domain. ARA-S was also found to activate KV7.1 and KV7.5 but not KV7.4, which instead was inhibited. Retigabine, a compound that activates the M-channel but has a different KV7 subtype selectivity compared to ARA-S, was used in combination with ARA-S to maintain a potent effect on the M-channel while limiting the activation of other KV7 channels.

In conclusion, the activating effect of PUFA analogs on KV7 channels may be helpful in the development of future drug candidates for diseases such as arrhythmia and epilepsy.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2020. p. 66
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1740
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:liu:diva-165684 (URN)10.3384/diss.diva-165684 (DOI)9789179298463 (ISBN)
Public defence
2020-06-05, Hasselquistsalen, Bulding 511, Campus US, Linköping, 13:00 (English)
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Available from: 2020-05-12 Created: 2020-05-12 Last updated: 2020-05-12Bibliographically approved

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