Manipulating the permeation of charged compounds through the MscL nanovalve

MscL is a bacterial mechanosensor that serves as a biological emergency release valve, releasing cytoplasmic solutes to the environment on osmotic downshock. Previous studies have recognized that this channel has properties that make it ideal for use as a triggered nanovalve for vesicular-based targeted drug-release devices. One can even change the modality of the sensor. Briefly, the introduction of charges into the MscL pore lumen gates the channel in the absence of membrane tension; thus, by inserting compounds that acquire a charge on exposure to an alternative stimulus, such as light or pH, into the pore of the channel, controllable nanoswitches that detect these alternative modalities have been engineered. However, a charge in the pore lumen could not only encourage actuation of the nanopore but also have a significant influence on the permeation of large charged compounds, which would thus have important implications for the efficiency of drug-release devices. In this study, we used in vivo and electrophysiological approaches to demonstrate that the introduction of a charge into pore lumen of MscL does indeed influence the permeation of charged molecules. These effects were more drastic for larger compounds and, surprisingly, were related to the orientation of the MscL channel in the membrane.