Abstract
The epithelial cell tight junction structure is the site of the transepithelial movement of solutes and water between epithelial cells (paracellular permeability). Paracellular permeability can be divided into two distinct pathways, the Pore Pathway mediating the movement of small ions and solutes and the Leak Pathway mediating the movement of large solutes. Claudin proteins form the basic paracellular permeability barrier and mediate the movement of small ions and solutes via the Pore Pathway. The Leak Pathway remains less understood. Several proteins have been implicated in mediating the Leak Pathway, including occludin, ZO proteins, tricellulin, and actin filaments, but the proteins comprising the Leak Pathway remain unresolved. Many aspects of the Leak Pathway, such as its molecular mechanism, its properties, and its regulation, remain controversial. In this review, we provide a historical background to the evolution of the Leak Pathway concept from the initial examinations of paracellular permeability. We then discuss current information about the properties of the Leak Pathway and present current theories for the Leak Pathway. Finally, we discuss some recent research suggesting a possible molecular basis for the Leak Pathway.
Highlights
La+3 ions are not transported into cells and can be precipitated into the electron dense lanthanum sulfate which can be detected by electron microscopy [5]. They demonstrated that La+3 permeates the tight junctions of both intestinal and gallbladder epithelia, supporting the idea that the tight junction is the site of the epithelial tissue paracellular permeability pathway
This leads to bursts of molecules entering the receiver fluid compartment. (b) The entire tight junction structure is disrupted at a specific locus macromolecules entering the receiver fluid compartment. (b) The entire tight junction structure is disrupted at a specific leading to formation of a continuous opening joining the donor and receiver fluid compartments
Manda et al [142] reported that expression of a deletion mutant occludin protein lacking a C-terminal sequence containing multiple serine, threonine, and tyrosine phosphorylation sites, called the Occludin Regulatory Motif (ORM), decreased occludin protein dynamic mobility in MDCK Type II renal epithelial (MDCK II) cells and in IEC6 intestinal epithelial cells
Summary
The concept of a barrier, the “terminal bar”, that restricts the movement of solutes and water through the paracellular pathway between epithelial cells dates back at least to Bizzozero [1]. La+3 ions are not transported into cells and can be precipitated into the electron dense lanthanum sulfate which can be detected by electron microscopy [5] They demonstrated that La+3 permeates the tight junctions of both intestinal and gallbladder epithelia, supporting the idea that the tight junction is the site of the epithelial tissue paracellular permeability pathway. It was previously shown that lanthanum ions did not permeate into the tight junctions of toad urinary bladder epithelia [4] and frog skin epithelia [6] Based on these and other observations, Machen et al [4] and Frömter and Diamond [7] proposed a categorization of epithelia as “leaky” or “tight” based on their relative permeability to small ions. This designation related solely to their relative permeability to small ions, the Pore Pathway, and was unrelated to permeability to larger molecules, the Leak Pathway (see below)
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