The control of permeability through the paracellular route has been paid great attention to for enhanced bioavailability of macromolecular and hydrophilic drugs. The paracellular permeability is controlled by tight junctions (TJ), and claudins are the major constituents of TJ. Despite numerous studies on TJ modulation, the dynamics is not well understood, although it could be crucial for clinical applications. Here, we studied the time (t) course of electrical conductivity (Σ) in a monolayer of Madin-Darby canine kidney (MDCK) and Caco-2 cells upon treatment with modulators, the C-terminus fragments of Clostridium perfringens enterotoxin (C-CPE) and sodium caprate (C10). For C-CPE treatment, Σ remains approximately constant, then starts increasing at t=t c (percolation threshold). For C10, on the other hand, Σ increases to 1.6-2.0 fold of the initial value, stays constant, and then starts increasing again for both MDCK and Caco-2 cells at t=t c . We find that this behavior can be explained within a framework of percolation, where Σ shows a logarithmic dependence on t−t c with the power of μ; μ denotes the critical exponent. We obtain μ=1.1-1.2 regardless of cell type or modulator. Notably, μ depends only on the dimensionality (d) of the system, and these values correspond to those for d=2. Percolation is thus the operative mechanism for the increase in Σ through TJ modulation. The findings provide fundamental knowledge, not only on controlled drug delivery, but also on bio-nanotechnologies including the fabrication of biological devices.Key words percolation analysis; tight junction; transepithelial electrical resistance; critical exponent; claudin; permeation-enhancing agent Drug delivery routes include transcellular and paracellular pathways. The permeability through the former for macromolecular and hydrophilic drugs is quite low. The control of permeability through the paracellular route has thus received a great deal of attention for enhanced bioavailability.1,2) The paracellular permeability across epithelial cells is controlled principally by tight junctions (TJ), which are located at the most apical portion of cell-cell contact points.3) Claudins are the major constituents of TJ and form a strand network. 4) A single TJ strand consists of a continuous array of small particles having a diameter of 5-10 nm, 4) and claudins between adjacent cells form the strand through trans-interaction. The barrier property of these strands depends strongly on the combination of claudin types between adjacent cells, 5) and hence, on cell types. In addition, TJ strands dynamically change their topology within <30 s. 6) For modulating TJ barrier functions, including permeability of molecules and transepithelial electrical resistance (TER), the C-terminus fragments of Clostridium perfringens enterotoxin (C-CPE) 4,7) and sodium caprate (C10) 8) have been extensively studied as absorption enhancers. Comprehensive reviews on the molecular basis of the structures, 9) as well as physiology and function 10) of TJs have been made. ...
Sec61β is the β subunit of the Sec61 translocon and is responsible for expression and delivery of basolateral membrane proteins, including claudins, major constituents of tight junction (TJ). In the present study, the effect of Sec61β overexpression on TJ barrier functions in Madin-Darby canine kidney (MDCK) cells were investigated by monitoring transepithelial electrical resistance (TER) and the expression and distribution of claudins. We adopted the time required by TER to reach 50% (T 1/2 ) as a measure of TJ modulation rate. Sec61β overexpression increased TER by post-transcriptionally upregulating claudin-4 expression and resulted in increased TER. Sec61β overexpression increased TJ modulation rates (lower T 1/2 ), in conjunction with enhanced delivery of claudin-4 from and to plasma membranes. Marked co-distribution and indirect association of claudin-4 with Sec61β were observed, contributing to the enhanced delivery of claudin-4. Thus, Sec61β may be a novel TJ modulation target, including barrier function and modulation rates for drug delivery systems.
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