title: Sodium caprate transiently opens claudin-5-containing barriers at tight junctions of epithelial and endothelial cells.
abstract: Claudin-5 is a tight junction (TJ) protein which limits the diffusion of small hydrophilic molecules. Thus, it represents a potential pharmacological target to improve drug delivery to the tissues protected by claudin-5-dependent barriers. Sodium caprate is known as an absorption enhancer which opens the paracellular space acting on TJ proteins and actin cytoskeleton. Its action on claudin-5 is not understood so far. Epithelial and endothelial systems were used to evaluate the effect of caprate on claudin-5 in TJ-free cells and on claudin-5 fully integrated in TJ. To this aim, confocal microscopy on live and fixed cells and isolated mouse brain capillaries, Western blotting and permeability assays were employed. Caprate reversibly reduced claudin-5 trans-interactions in TJ-free human embryonic kidney-293 cells expressing claudin-5-YFP. It decreased the membranous claudin-5 and the F-actin content in Madin-Darby canine kidney-II cells expressing Flag-claudin-5, thereby increasing the permeability to the small molecule lucifer yellow. Interestingly, zonula occludens protein 1 (ZO-1), which links transmembranous TJ proteins to the actin cytoskeleton, was not affected by caprate treatment. Similarly, endogenous claudin-5 in the membrane of brain endothelia was displaced together with F-actin, whereas ZO-1 remained unaffected. Caprate transiently opens the paracellular space, reducing the intercellular claudin-5/claudin-5 interactions and the polymerized actin at the perijunctional region of endothelial and epithelial cells. In conclusion, the study further elucidates the cellular effects of caprate at the tight junctions.
authors: Leibniz-Institut für Molekulare Pharmakologie, FMP, 13125 Berlin, Germany.
authors: G
authors: G
authors: Del Vecchio
authors: C
authors: C
authors: Tscheik
authors: K
authors: K
authors: Tenz
authors: H C
authors: HC
authors: Helms
authors: L
authors: L
authors: Winkler
authors: R
authors: R
authors: Blasig
authors: I E
authors: IE
authors: Blasig
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D062507:Claudin-5 / Q000378:metabolism*; D003652:Decanoic Acids / Q000494:pharmacology*; D004285:Dogs; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability / Q000187:drug effects; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D000199:Actins; D062507:Claudin-5; D003652:Decanoic Acids; D007546:Isoquinolines; D008565:Membrane Proteins; D062826:Zonula Occludens-1 Protein; C031071:decanoic acid; C017475:lucifer yellow