Heterogeneity of Claudin Expression by Alveolar Epithelial Cells

Wang, Fushan; Daugherty, Brandy L.; Keise, Lisa L.; Wei, Zhengyu; Foley, Joseph; Savani, Rashmin C.; Koval, Michael

doi:10.1165/rcmb.2002-0180oc

Cited by 138 publications

(140 citation statements)

References 52 publications

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“…Our original identification of MBEC1/claudin-5 mRNA and protein expression by the endothelial cells of the BBB (8) has subsequently been confirmed by others (34,41,42). In addition to BBB and other endothelial cells, our studies (8) and those of others (32,35,45,56) have revealed claudin-5 expression in epithelial cells as well as other specialized cell types, including pancreatic acinar cells (45) and myelinating Schwann cells in nerves (44).…”

Section: Discussionsupporting

confidence: 70%

Selective Decrease in Paracellular Conductance of Tight Junctions: Role of the First Extracellular Domain of Claudin-5

Wen

Watry

Marcondes

et al. 2004

Molecular and Cellular Biology

187

143

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Claudin-5 is a protein component of many endothelial tight junctions, including those at the blood-brain barrier, a barrier that limits molecular exchanges between the central nervous system and the circulatory system. To test the contribution of claudin-5 to this barrier function of tight junctions, we expressed murine claudin-5 in Madin-Darby canine kidney II cells. The result was a fivefold increase in transepithelial resistance in claudin-5 transductants and a reduction in conductance of monovalent cations. However, the paracellular flux of neither neutral nor charged monosaccharides was significantly changed in claudin-5 transductants compared to controls. Therefore, expression of claudin-5 selectively decreased the permeability to ions. Additionally, site-directed mutations of particular amino acid residues in the first extracellular domain of claudin-5 altered the properties of the tight junctions formed in response to claudin-5 expression. In particular, the conserved cysteines were crucial: mutation of either cysteine abolishted the ability of claudin-5 to increase transepithelial resistance, and mutation of Cys 64 strikingly increased the paracellular flux of monosaccharides. These new insights into the functions of claudin-5 at the molecular level in tight junctions may account for some aspects of the blood-brain barrier's selective permeability.

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Section: Discussionsupporting

confidence: 70%

Selective Decrease in Paracellular Conductance of Tight Junctions: Role of the First Extracellular Domain of Claudin-5

Wen

Watry

Marcondes

et al. 2004

Molecular and Cellular Biology

187

143

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“…Reduced expression of claudin-5 as seen in the present study has been associated with increased permeability in several previous studies (Kirk et al, 2003;Kitajima et al, 2006;Kniesel and Wolburg, 2000;Tsukita and Furuse, 1998). While transfection of claudin-5 into epithelial cells with a low electrical resistance enhances barrier function (Amasheh et al, 2005), overexpression of claudin-5 results in a loss of barrier function and increased permeability and paracellular volume of distribution (Coyne et al, 2003;Kojima et al, 2002;Wang et al, 2003). Knocking out the claudin-5 gene is lethal within 10 h of birth, and BBB TJs become more permeable to molecules <800 Da, but not larger (Nitta et al, 2003).…”

Section: Discussionsupporting

confidence: 66%

Biphasic cytoarchitecture and functional changes in the BBB induced by chronic inflammatory pain

et al. 2006

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The blood-brain barrier (BBB) is a dynamic system which maintains brain homeostasis and limits CNS penetration via interactions of transmembrane and intracellular proteins. Inflammatory pain (IP) is a condition underlying several diseases with known BBB perturbations, including stroke, Parkinson's, multiple sclerosis and Alzheimer's. Exploring the underlying pathology of chronic IP, we demonstrated alterations in BBB paracellular permeability with correlating changes in tight junction (TJ) proteins: occludin and claudin-5. The present study examines the IP-induced molecular changes leading to a loss in functional BBB integrity. IP was induced by injection of Complete Freund's Adjuvant (CFA) into the plantar surface of the right hindpaw of female Sprague-Dawley rats. Inflammation and hyperalgesia were confirmed, and BBB paracellular permeability was assessed by in situ brain perfusion of [ 14 C]sucrose (paracellular diffusion marker). The permeability of the BBB was significantly increased at 24 and 72 h post-CFA. Analysis of the TJ proteins, which control the paracellular pathway, demonstrated decreased claudin-5 expression at 24 h, and an increase at 48 and 72 h post-injection. Occludin expression was significantly decreased 72 h post-CFA. Expression of junction adhesion molecule-1 (JAM-1) increased 48 h and decreased by 72 h post-CFA. Confocal microscopy demonstrated continuous expression of both occludin and JAM-1, each co-localizing with ZO-1. The increased claudin-5 expression was not limited to the junction. These results provide evidence that chronic IP causes dramatic alterations in specific cytoarchitectural proteins and demonstrate alterations in molecular properties during CFA, resulting in significant changes in BBB paracellular permeability.

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“…For instance, if heterotypic incompatibility (e.g. between claudin-5 and claudin-4) is a dominant interaction in lung epithelia, then increased claudin-5 expression would be expected to compromise tight junction integrity, as previously observed (31). Conversely, in the endothelium, claudin-5 may be compatible with the other major endothelial claudin, claudin-12 (34).…”

Section: Discussionmentioning

confidence: 78%

Regulation of Heterotypic Claudin Compatibility

Daugherty

Ward

Smith

et al. 2007

Journal of Biological Chemistry

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140

154

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Tissue barrier function is directly mediated by tight junction transmembrane proteins known as claudins. Cells that form tight junctions typically express multiple claudin isoforms which suggests that heterotypic (head-to-head) binding between different claudin isoforms may play a role in regulating paracellular permeability. However, little is known about motifs that control heterotypic claudin compatibility. We found that although claudin-3 and claudin-4 were heteromerically compatible when expressed in the same cell, they did not heterotypically interact despite having extracellular loop (EL) domains that are highly conserved at the amino acid level. Claudin-1 and -5, which were heterotypically compatible with claudin-3, did not heterotypically bind to claudin-4. In contrast, claudin-4 chimeras containing either the first EL domain or the second EL domain of claudin-3 were able to heterotypically bind to claudin-1, claudin-3, and claudin-5. Moreover, a single point mutation in the first extracellular loop domain of claudin-3 to convert Asn 44 to the corresponding amino acid in claudin-4 (Thr) produced a claudin capable of heterotypic binding to claudin-4 while still retaining the ability to bind to claudin-1 and -5. Thus, control of heterotypic claudin-claudin interactions is sensitive to small changes in the EL domains.

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Heterogeneity of Claudin Expression by Alveolar Epithelial Cells

Cited by 138 publications

References 52 publications

Selective Decrease in Paracellular Conductance of Tight Junctions: Role of the First Extracellular Domain of Claudin-5

Selective Decrease in Paracellular Conductance of Tight Junctions: Role of the First Extracellular Domain of Claudin-5

Biphasic cytoarchitecture and functional changes in the BBB induced by chronic inflammatory pain

Regulation of Heterotypic Claudin Compatibility

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