The antiarrhythmic compound efsevin directly modulates voltage-dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca2+ uptake

被引:16
|
作者
Wilting, Fabiola [1 ]
Kopp, Robin [1 ]
Gurnev, Philip A. [2 ]
Schedel, Anna [1 ]
Dupper, Nathan J. [3 ]
Kwon, Ohyun [3 ]
Nicke, Annette [1 ]
Gudermann, Thomas [1 ,4 ]
Schredelseker, Johann [1 ]
机构
[1] Ludwig Maximilians Univ Munchen, Walther Straub Inst Pharmacol & Toxicol, Fac Med, Munich, Germany
[2] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Transport, NIH, Bethesda, MD USA
[3] Univ Calif Los Angeles, Dept Chem & Biochem, 405 Hilgard Ave, Los Angeles, CA 90024 USA
[4] Deutsch Zentrum Herz Kreislauf Forsch DZHK, Partner Site Munich Heart Alliance MHA, Munich, Germany
关键词
VDAC2; RETICULUM; INSIGHTS; ISOFORM; CLOSURE; BAK;
D O I
10.1111/bph.15022
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 alpha-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 Ca2+ 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 Ca2+ transfer. This study sheds new light on the function of VDAC2 and provides a basis for structure-aided chemical optimization of efsevin.
引用
收藏
页码:2947 / 2958
页数:12
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