The antiarrhythmic compound efsevin directly modulates voltage-dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
12
04
2019
revised:
20
01
2020
accepted:
29
01
2020
pubmed:
15
2
2020
medline:
22
6
2021
entrez:
15
2
2020
Statut:
ppublish
Résumé
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. 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. 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 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
Sections du résumé
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
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
Identifiants
pubmed: 32059260
doi: 10.1111/bph.15022
pmc: PMC7279994
doi:
Substances chimiques
Voltage-Dependent Anion Channel 2
0
Zebrafish Proteins
0
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2947-2958Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM071779
Pays : United States
Organisme : Deutsche Forschungsgemeinschaft
ID : SCHR 1471/1-1
Informations de copyright
© 2020 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
Références
Sci Rep. 2016 Sep 13;6:32994
pubmed: 27620692
Biochim Biophys Acta. 2007 Oct;1768(10):2510-5
pubmed: 17617374
Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17705-10
pubmed: 16314582
J Comput Chem. 2009 Dec;30(16):2785-91
pubmed: 19399780
Biochem J. 2012 Nov 1;447(3):371-9
pubmed: 22867515
J Biol Chem. 2014 May 2;289(18):12566-77
pubmed: 24627492
Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2979-84
pubmed: 9501201
J Comput Chem. 2010 Jan 30;31(2):455-61
pubmed: 19499576
Biochem Biophys Res Commun. 2005 Jan 28;326(4):799-804
pubmed: 15607740
Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17742-7
pubmed: 18988731
Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17699-704
pubmed: 16314583
Cell Death Differ. 2012 Feb;19(2):267-73
pubmed: 21720385
J Cell Biol. 2002 Nov 25;159(4):613-24
pubmed: 12438411
Br J Pharmacol. 2020 Jul;177(13):2947-2958
pubmed: 32059260
J Membr Biol. 1989 Oct;111(2):103-11
pubmed: 2482359
PLoS One. 2012;7(10):e47938
pubmed: 23110136
Nature. 2004 Jan 22;427(6972):360-4
pubmed: 14737170
Biochim Biophys Acta Bioenerg. 2018 Apr;1859(4):270-279
pubmed: 29408701
Oncotarget. 2016 Jan 19;7(3):2249-68
pubmed: 26760765
Dev Dyn. 2007 Nov;236(11):3088-99
pubmed: 17937395
Br J Pharmacol. 2018 Apr;175(7):987-993
pubmed: 29520785
Front Chem. 2018 Apr 06;6:108
pubmed: 29682501
Nucleic Acids Res. 2018 Jan 4;46(D1):D1091-D1106
pubmed: 29149325
Structure. 2012 Sep 5;20(9):1540-9
pubmed: 22841291
Elife. 2015 Jan 15;4:
pubmed: 25588501
J Am Chem Soc. 2014 Aug 27;136(34):11890-3
pubmed: 25099350
JACC Basic Transl Sci. 2017 Dec;2(6):737-747
pubmed: 29354781
Science. 2003 Jul 25;301(5632):513-7
pubmed: 12881569
J Vis Exp. 2012 Jan 09;(59):e3383
pubmed: 22257923
Biochim Biophys Acta. 2012 Jun;1818(6):1477-85
pubmed: 22051019
Biosci Rep. 2009 Jul 22;29(6):351-62
pubmed: 18976238
Cell Calcium. 2011 Feb;49(2):136-43
pubmed: 21241999
Biochim Biophys Acta. 2016 Oct;1863(10):2503-14
pubmed: 27116927
J Cell Biol. 2006 Dec 18;175(6):901-11
pubmed: 17178908
Circulation. 2018 Mar 20;137(12):e67-e492
pubmed: 29386200
J Biol Chem. 2012 Aug 24;287(35):29589-98
pubmed: 22763701
Nucleic Acids Res. 2018 Jul 2;46(W1):W296-W303
pubmed: 29788355
J Chem Inf Model. 2011 Oct 24;51(10):2778-86
pubmed: 21919503
J Mol Biol. 2010 Feb 26;396(3):580-92
pubmed: 20005234
Biochim Biophys Acta. 2015 Dec;1848(12):3188-96
pubmed: 26407725
Eur Biophys J. 2006 Dec;36(1):57-66
pubmed: 17021806
Cell Death Differ. 2014 Dec;21(12):1925-35
pubmed: 25146925
Biochim Biophys Acta. 2016 Jun;1858(6):1350-61
pubmed: 26997586