TY - JOUR
T1 - Sites and functional consequence of VDAC-alkylphenol anesthetic interactions
AU - Weiser, Brian P.
AU - Bu, Weiming
AU - Wong, David
AU - Eckenhoff, Roderic G.
N1 - Funding Information:
We thank Tatiana Rostovtseva and Oscar Teijido for their excellent guidance with VDAC electrophysiology techniques, and we thank Michael Weinrich for performing the gramicidin A recordings. This work was partially supported by the Solomon and Catherine Erulkar Traveling Fellowship awarded to B.P.W. Other support was provided by the National Institutes of Health , including through Grants F31-NS080519 and P01-GM055876 .
Publisher Copyright:
© 2014 Federation of European Biochemical Societies. All rights reserved.
PY - 2014/11/28
Y1 - 2014/11/28
N2 - General anesthetics have previously been shown to bind mitochondrial VDAC. Here, using a photoactive analog of the anesthetic propofol, we determined that alkylphenol anesthetics bind to Gly56 and Val184 on rat VDAC1. By reconstituting rat VDAC into planar bilayers, we determined that propofol potentiates VDAC gating with asymmetry at the voltage polarities; in contrast, propofol does not affect the conductance of open VDAC. Additional experiments showed that propofol also does not affect gramicidin A properties that are sensitive to lipid bilayer mechanics. Together, this suggests propofol affects VDAC function through direct protein binding, likely at the lipid-exposed channel surface, and that gating can be modulated by ligand binding to the distal ends of VDAC β-strands where Gly56 and Val184 are located.
AB - General anesthetics have previously been shown to bind mitochondrial VDAC. Here, using a photoactive analog of the anesthetic propofol, we determined that alkylphenol anesthetics bind to Gly56 and Val184 on rat VDAC1. By reconstituting rat VDAC into planar bilayers, we determined that propofol potentiates VDAC gating with asymmetry at the voltage polarities; in contrast, propofol does not affect the conductance of open VDAC. Additional experiments showed that propofol also does not affect gramicidin A properties that are sensitive to lipid bilayer mechanics. Together, this suggests propofol affects VDAC function through direct protein binding, likely at the lipid-exposed channel surface, and that gating can be modulated by ligand binding to the distal ends of VDAC β-strands where Gly56 and Val184 are located.
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U2 - 10.1016/j.febslet.2014.10.009
DO - 10.1016/j.febslet.2014.10.009
M3 - Article
C2 - 25448677
AN - SCOPUS:84910629186
SN - 0014-5793
VL - 588
SP - 4398
EP - 4403
JO - FEBS Letters
JF - FEBS Letters
IS - 23
ER -