Mode of action of claudin peptidomimetics in the transient opening of cellular tight junction barriers

Staat, Christian; Coisne, Caroline Marie; Dabrowski, Sebastian; Stamatovic, Svetlana M; Andjelkovic, Anuska V; Wolburg, Hartwig; Engelhardt, Britta; Blasig, Ingolf E (2015). Mode of action of claudin peptidomimetics in the transient opening of cellular tight junction barriers. Biomaterials, 54, pp. 9-20. Elsevier 10.1016/j.biomaterials.2015.03.007

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In epithelial/endothelial barriers, claudins form tight junctions, seal the paracellular cleft, and limit the uptake of solutes and drugs. The peptidomimetic C1C2 from the C-terminal half of claudin-1's first extracellular loop increases drug delivery through epithelial claudin-1 barriers. However, its molecular and structural mode of action remains unknown. In the present study, >100 μM C1C2 caused paracellular opening of various barriers with different claudin compositions, ranging from epithelial to endothelial cells, preferentially modulating claudin-1 and claudin-5. After 6 h incubation, C1C2 reversibly increased the permeability to molecules of different sizes; this was accompanied by redistribution of claudins and occludin from junctions to cytosol. Internalization of C1C2 in epithelial cells depended on claudin-1 expression and clathrin pathway, whereby most C1C2 was retained in recyclosomes >2 h. In freeze-fracture electron microscopy, C1C2 changed claudin-1 tight junction strands to a more parallel arrangement and claudin-5 strands from E-face to P-face association - drastic and novel effects. In conclusion, C1C2 is largely recycled in the presence of a claudin, which explains the delayed onset of barrier and junction loss, the high peptide concentration required and the long-lasting effect. Epithelial/endothelial barriers are specifically modulated via claudin-1/claudin-5, which can be targeted to improve drug delivery.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

UniBE Contributor:

Coisne, Caroline Marie and Engelhardt, Britta

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0142-9612

Publisher:

Elsevier

Language:

English

Submitter:

Ursula Zingg-Zünd

Date Deposited:

14 Mar 2016 15:06

Last Modified:

14 Mar 2016 15:06

Publisher DOI:

10.1016/j.biomaterials.2015.03.007

PubMed ID:

25907035

Uncontrolled Keywords:

Brain endothelial cells; Controlled drug release; Endocytosis; Freeze-fracture electron microscopy; Peptidomimetics; Tight junction proteins

BORIS DOI:

10.7892/boris.77330

URI:

https://boris.unibe.ch/id/eprint/77330

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