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The antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca(2+) uptake

BACKGROUND AND PURPOSE: The synthetic compound efsevin was recently identified to suppress arrhythmogenesis in models of cardiac arrhythmia, making it a promising candidate for antiarrhythmic therapy. Its activity was shown to be dependent on the voltage‐dependent anion channel 2 (VDAC2) in the oute...

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Autores principales: Wilting, Fabiola, Kopp, Robin, Gurnev, Philip A., Schedel, Anna, Dupper, Nathan J., Kwon, Ohyun, Nicke, Annette, Gudermann, Thomas, Schredelseker, Johann
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279994/
https://www.ncbi.nlm.nih.gov/pubmed/32059260
http://dx.doi.org/10.1111/bph.15022
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author Wilting, Fabiola
Kopp, Robin
Gurnev, Philip A.
Schedel, Anna
Dupper, Nathan J.
Kwon, Ohyun
Nicke, Annette
Gudermann, Thomas
Schredelseker, Johann
author_facet Wilting, Fabiola
Kopp, Robin
Gurnev, Philip A.
Schedel, Anna
Dupper, Nathan J.
Kwon, Ohyun
Nicke, Annette
Gudermann, Thomas
Schredelseker, Johann
author_sort Wilting, Fabiola
collection PubMed
description BACKGROUND AND PURPOSE: The synthetic compound efsevin was recently identified to suppress arrhythmogenesis in models of cardiac arrhythmia, making it a promising candidate for antiarrhythmic therapy. Its activity was shown to be dependent on the voltage‐dependent anion channel 2 (VDAC2) in the outer mitochondrial membrane. Here, we investigated the molecular mechanism of the efsevin–VDAC2 interaction. EXPERIMENTAL APPROACH: To evaluate the functional interaction of efsevin and VDAC2, we measured currents through recombinant VDAC2 in planar lipid bilayers. Using molecular ligand‐protein docking and mutational analysis, we identified the efsevin binding site on VDAC2. Finally, physiological consequences of the efsevin‐induced modulation of VDAC2 were analysed in HL‐1 cardiomyocytes. KEY RESULTS: In lipid bilayers, efsevin reduced VDAC2 conductance and shifted the channel's open probability towards less anion‐selective closed states. Efsevin binds to a binding pocket formed by the inner channel wall and the pore‐lining N‐terminal α‐helix. Exchange of amino acids N207, K236 and N238 within this pocket for alanines abolished the channel's efsevin‐responsiveness. Upon heterologous expression in HL‐1 cardiomyocytes, both channels, wild‐type VDAC2 and the efsevin‐insensitive VDAC2(AAA) restored mitochondrial Ca(2+) uptake, but only wild‐type VDAC2 was sensitive to efsevin. CONCLUSION AND IMPLICATIONS: In summary, our data indicate a direct interaction of efsevin with VDAC2 inside the channel pore that leads to modified gating and results in enhanced SR‐mitochondria Ca(2+) transfer. This study sheds new light on the function of VDAC2 and provides a basis for structure‐aided chemical optimization of efsevin.
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spelling pubmed-72799942020-06-10 The antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca(2+) uptake Wilting, Fabiola Kopp, Robin Gurnev, Philip A. Schedel, Anna Dupper, Nathan J. Kwon, Ohyun Nicke, Annette Gudermann, Thomas Schredelseker, Johann Br J Pharmacol Research Papers BACKGROUND AND PURPOSE: The synthetic compound efsevin was recently identified to suppress arrhythmogenesis in models of cardiac arrhythmia, making it a promising candidate for antiarrhythmic therapy. Its activity was shown to be dependent on the voltage‐dependent anion channel 2 (VDAC2) in the outer mitochondrial membrane. Here, we investigated the molecular mechanism of the efsevin–VDAC2 interaction. EXPERIMENTAL APPROACH: To evaluate the functional interaction of efsevin and VDAC2, we measured currents through recombinant VDAC2 in planar lipid bilayers. Using molecular ligand‐protein docking and mutational analysis, we identified the efsevin binding site on VDAC2. Finally, physiological consequences of the efsevin‐induced modulation of VDAC2 were analysed in HL‐1 cardiomyocytes. KEY RESULTS: In lipid bilayers, efsevin reduced VDAC2 conductance and shifted the channel's open probability towards less anion‐selective closed states. Efsevin binds to a binding pocket formed by the inner channel wall and the pore‐lining N‐terminal α‐helix. Exchange of amino acids N207, K236 and N238 within this pocket for alanines abolished the channel's efsevin‐responsiveness. Upon heterologous expression in HL‐1 cardiomyocytes, both channels, wild‐type VDAC2 and the efsevin‐insensitive VDAC2(AAA) restored mitochondrial Ca(2+) uptake, but only wild‐type VDAC2 was sensitive to efsevin. CONCLUSION AND IMPLICATIONS: In summary, our data indicate a direct interaction of efsevin with VDAC2 inside the channel pore that leads to modified gating and results in enhanced SR‐mitochondria Ca(2+) transfer. This study sheds new light on the function of VDAC2 and provides a basis for structure‐aided chemical optimization of efsevin. John Wiley and Sons Inc. 2020-03-25 2020-07 /pmc/articles/PMC7279994/ /pubmed/32059260 http://dx.doi.org/10.1111/bph.15022 Text en © 2020 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Papers
Wilting, Fabiola
Kopp, Robin
Gurnev, Philip A.
Schedel, Anna
Dupper, Nathan J.
Kwon, Ohyun
Nicke, Annette
Gudermann, Thomas
Schredelseker, Johann
The antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca(2+) uptake
title The antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca(2+) uptake
title_full The antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca(2+) uptake
title_fullStr The antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca(2+) uptake
title_full_unstemmed The antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca(2+) uptake
title_short The antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca(2+) uptake
title_sort antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial ca(2+) uptake
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279994/
https://www.ncbi.nlm.nih.gov/pubmed/32059260
http://dx.doi.org/10.1111/bph.15022
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