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Department of Pharmacology

 
Author(s): 
Geyer, M, Huang, F, Sun, Y, Vogel, SM, Malik, AB, Taylor, CW, Komarova, YA
Abstract: 

The mechanisms by which the microtubule cytoskeleton regulates the permeability of endothelial barrier are not well understood. Here, we demonstrate thatmicrotubule-associated end-binding protein 3 (EB3), a core component of the microtubule plus-end protein complex, binds to inositol 1,4,5-trisphosphate receptors (IP3Rs) through an S/TxIP EB-binding motif. In endothelial cells, α-thrombin, a pro-inflammatory mediator that stimulates phospholipase Cβ, increases the cytosolic Ca2+ concentration and elicits clustering of IP3R3s. These responses, and the resulting Ca2+-dependent phosphorylation of myosin light chain, are prevented by depletion of either EB3 or mutation of the TxIP motif of IP3R3 responsible for mediating its binding to EB3. We also show that selective EB3 gene deletion in endothelial cells of mice abrogates α-thrombin-induced increase in endothelial permeability. We conclude that the EB3-mediated interaction of IP3Rs with microtubules controls the assembly of IP3Rs into effective Ca2+ signaling clusters, which thereby regulate microtubule-dependent endothelial permeability.

Publication ID: 
698250
Published date: 
7 July 2015
Publication source: 
scopus
Publication type: 
Journal articles
Journal name: 
Cell Reports
Publication volume: 
12
Publisher: 
Parent title: 
Edition: 
Publication number: