307 research outputs found
The antiarrhythmic compound efsevin directly modulates voltageâdependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca2+ 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 voltageâdependent anion channel 2 (VDAC2) in the outer mitochondrial membrane. Here, we investigated the molecular mechanism of the efsevinâVDAC2 interaction.
Experimental Approach
To evaluate the functional interaction of efsevin and VDAC2, we measured currents through recombinant VDAC2 in planar lipid bilayers. Using molecular ligandâprotein docking and mutational analysis, we identified the efsevin binding site on VDAC2. Finally, physiological consequences of the efsevinâinduced modulation of VDAC2 were analysed in HLâ1 cardiomyocytes.
Key Results
In lipid bilayers, efsevin reduced VDAC2 conductance and shifted the channel's open probability towards less anionâselective closed states. Efsevin binds to a binding pocket formed by the inner channel wall and the poreâlining Nâterminal αâhelix. Exchange of amino acids N207, K236 and N238 within this pocket for alanines abolished the channel's efsevinâresponsiveness. Upon heterologous expression in HLâ1 cardiomyocytes, both channels, wildâtype VDAC2 and the efsevinâinsensitive VDAC2AAA restored mitochondrial Ca2+ uptake, but only wildâtype 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 SRâmitochondria Ca2+ transfer. This study sheds new light on the function of VDAC2 and provides a basis for structureâaided chemical optimization of efsevin
Orbital character of O 2p unoccupied states near the Fermi level in CrO2
The orbital character, orientation, and magnetic polarization of the O 2
unoccupied states near the Fermi level () in CrO was determined using
polarization-dependent X-ray absorption spectroscopy (XAS) and X-ray magnetic
circular dichroism (XMCD) from high-quality, single-crystal films. A sharp peak
observed just above is excited only by the electric field vector () normal to the tetragonal -axis, characteristic of a narrow band
( 0.7 eV bandwidth) constituted from O 2 orbitals perpendicular to
(O 2) hybridized with Cr 3 states. By comparison
with band-structure and configuration-interaction (CI) cluster calculations our
results support a model of CrO as a half-metallic ferromagnet with large
exchange-splitting energy ( 3.0 eV) and
substantial correlation effects.Comment: 4 pages, 3 figures, accepted for publication in Phys. Rev. B Rapid
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