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.
Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, United States.
FEBS Lett. 2014 Nov 28;588(23):4398-403. doi: 10.1016/j.febslet.2014.10.009. Epub 2014 Oct 18.
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.
先前的研究表明，全身麻醉剂可与线粒体 VDAC 结合。在这里，我们使用一种光活性的麻醉剂异丙酚类似物，确定烷基酚类麻醉剂结合到大鼠 VDAC1 的 Gly56 和 Val184。通过将大鼠 VDAC 重新构成平面双层，我们确定异丙酚在电压极性下使 VDAC 门控产生不对称性；相比之下，异丙酚不影响开放 VDAC 的电导率。进一步的实验表明，异丙酚也不影响对脂质双层力学敏感的短杆菌肽 A 的性质。总的来说，这表明异丙酚通过直接蛋白结合（可能在脂质暴露的通道表面）影响 VDAC 的功能，并且配体结合到位于 Gly56 和 Val184 处的 VDAC β-链的远端可以调节门控。
