title: Sites and functional consequence of VDAC-alkylphenol anesthetic interactions.
abstract: 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.
authors.affiliation: Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, United States; Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, United States.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Weiser
authors.affiliation: Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, United States.
authors.forename: Weiming
authors.initials: W
authors.lastname: Bu
authors.affiliation: Drexel University College of Medicine, Philadelphia, PA 19129, United States.
authors.forename: David
authors.initials: D
authors.lastname: Wong
authors.affiliation: Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, United States. Electronic address: roderic.eckenhoff@uphs.upenn.edu.
authors.forename: Roderic G
authors.initials: RG
authors.lastname: Eckenhoff
mesh_terms: D018681:Anesthetics, General / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D005260:Female; D008958:Models, Molecular; D010636:Phenols / Q000737:chemistry* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D051381:Rats; D050994:Voltage-Dependent Anion Channels / Q000737:chemistry / Q000378:metabolism*
chemical_list: D018681:Anesthetics, General; D010636:Phenols; D050994:Voltage-Dependent Anion Channels
keywords: Azi-propofol; Photolabeling; Propofol; Voltage-dependent anion channel