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Tight Junctions in BBB

The TJs are multiprotein complexes between brain microvascular endothelial cells providing closely approaching intercellular connections. TJs are the major complex forming the BBB and are the most important structure underlying the normal physiology of the BBB. TJs in the BBB consist of several proteins, which include occlu- din, [26], claudin-1, claudin-3, claudin-5, claudin-10, and claudin-12, and junctional adhesion molecules (JAM-A, JAM-B, and JAM-C). Furthermore, there are important cytoplasmic scaffolding proteins that link TJs to cortical actin filaments such as zonula occludens (ZO)-linker proteins 1 and 2 (ZO-3 is not expressed by BECs) [7, 27]. Loss of claudin-3 in BBB TJ in EAE [28], in which BBB integrity is compromised, suggests an important role of claudin-3 in maintaining BBB TJ integrity. Claudin-3 is also distinctly localized to TJ in hCMEC/D3 cells, which are widely used as an in vitro model of human BBB [29]. Occludin and claudin-5 and claudin- 11 are “tetraspan” transmembrane proteins (four transmembrane helices and two extracellular loops) known as myelin and lymphocyte protein (MAL) and related proteins for vesicle trafficking and membrane link (MARVEL) domain. The second extracellular loop of occludin contains the LYHY motif, which mediates occludin’s role in cell-cell adhesion contributing to barrier function [30] as well as leukocyte emigration [5]. Activated immune cells also express occludin in some cases - which may permit them to link with occludin of BECs of BBB - ultimately allowing passage of these immune cells across tight junctions [31]. These proteins interact with various proteins on the cytoplasmic side of the membrane. For example, the extended C-terminus is essential for occludin dimerization as well as its interaction with ZO-1. These domains also interact with various kinases such as protein kinase C isoforms, tyrosine kinases, and phosphoinositol 3 kinase (PI3 kinase) as well as tyrosine phosphatases [32]. The reversible phosphorylation state of occludin and claudin as well as the abundance of these proteins is understood to be a key aspect of barrier function controlling the organization and barrier of endothelial tight junctions [33-36]. Another family of proteins localized in endothelial TJ is the JAMs. All three JAMs (JAM-A, JAM-B, and JAM-C) may be involved in leukocyte migration - for example, JAM-A mediates T cell migration by binding to LFA-1 [37]. TJ protein mutations or elimination leads to the breakdown of BBB and is functionally linked with some neurological disorders including band-like calcification with simplified gyration and polymicrogyria (BLC-PMG) [38]. Lastly, the tricellular and bicellular junctions in CEC appear to contain different components, with lipolysis-stimulated lipoprotein receptor (LSR)/angulin-1 recently defined as a tricellular tight junction protein contributing to the formation of the BBB [39].

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