Transmembrane proteins of the tight junctions at the blood–brain barrier: Structural and functional aspects

Farquhar, 1963, Junctional complexes in various epithelia, J Cell Biol, 17, 375, 10.1083/jcb.17.2.375 Schulze, 1993, Immunohistochemical localization of adherens junction components in blood–brain barrier microvessels of the rat, J Cell Sci, 104, 773, 10.1242/jcs.104.3.773 Wolburg, 1994, Modulation of tight junction structure in blood–brain barrier endothelial cells. Effects of tissue culture, second messengers and cocultured astrocytes, J Cell Sci, 107, 1347, 10.1242/jcs.107.5.1347 Liebner, 2000, Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme, Acta Neuropathol (Berl), 100, 323, 10.1007/s004010000180 Morita, 1999, Endothelial claudin: claudin-5/TMVCF constitutes tight junction strands in endothelial cells, J Cell Biol, 147, 185, 10.1083/jcb.147.1.185 Piontek, 2007, Formation of tight junction: determinants of homophilic interaction between classic claudins, FASEB J, 22, 148 Cording, 2013, In tight junctions, claudins regulate the interactions between occludin, tricellulin and marvelD3, which, inversely, modulate claudin oligomerization, J Cell Sci, 126, 554, 10.1242/jcs.114306 Piontek, 2011, Elucidating the principles of the molecular organization of heteropolymeric tight junction strands, Cell Mol Life Sci, 68, 3903, 10.1007/s00018-011-0680-z Kaufmann, 2012, Visualization and quantitative analysis of reconstituted tight junctions using localization microscopy, PLOS ONE, 7, 10.1371/journal.pone.0031128 Ohtsuki, 2007, Exogenous expression of claudin-5 induces barrier properties in cultured rat brain capillary endothelial cells, J Cell Physiol, 210, 81, 10.1002/jcp.20823 Ohtsuki, 2008, mRNA expression levels of tight junction protein genes in mouse brain capillary endothelial cells highly purified by magnetic cell sorting, J Neurochem, 104, 147 Raleigh, 2010, Tight junction-associated MARVEL proteins marvelD3, tricellulin, and occludin have distinct but overlapping functions, Mol Biol Cell, 21, 1200, 10.1091/mbc.E09-08-0734 Steed, 2009, Identification of marvelD3 as a tight junction-associated transmembrane protein of the occludin family, BMC Cell Biol, 10, 95, 10.1186/1471-2121-10-95 del Vecchio, 2012, Sodium caprate transiently opens claudin-5-containing barriers at tight junctions of epithelial and endothelial cells, Mol Pharm, 9, 2523, 10.1021/mp3001414 Mariano, 2013, Tricellulin expression in brain endothelial and neural cells, Cell Tissue Res, 351, 397, 10.1007/s00441-012-1529-y Iwamoto, 2014, Localization of angulin-1/LSR and tricellulin at tricellular contacts of brain and retinal endothelial cells in vivo, Cell Struct Funct, 39, 1, 10.1247/csf.13015 Kniesel, 1996, Development of blood–brain barrier tight junctions in the rat cortex, Dev Brain Res, 96, 229, 10.1016/0165-3806(96)00117-4 Butt, 1990, Electrical resistance across the blood–brain barrier in anaesthetized rats: a developmental study, J Physiol, 429, 47, 10.1113/jphysiol.1990.sp018243 Stewart, 1987, Interendothelial junctional changes underlie the developmental ‘tightening’ of the blood–brain barrier, Brain Res, 429, 271, 10.1016/0165-3806(87)90107-6 Inai, 2010, The protoplasmic or exoplasmic face association of tight junction particles cannot predict paracellular permeability or heterotypic claudin compatibility, Eur J Cell Biol, 89, 547, 10.1016/j.ejcb.2010.01.003 Furuse, 1993, Occludin – a novel integral membrane-protein localizing at tight junctions, J Cell Biol, 123, 1777, 10.1083/jcb.123.6.1777 Ikenouchi, 2005, Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells, J Cell Biol, 171, 939, 10.1083/jcb.200510043 Yaffe, 2012, The MARVEL transmembrane motif of occludin mediates oligomerization and targeting to the basolateral surface in epithelia, J Cell Sci, 125, 3545, 10.1242/jcs.100289 Krug, 2009, Tricellulin forms a barrier to macromolecules in tricellular tight junctions without affecting ion permeability, Mol Biol Cell, 20, 3713, 10.1091/mbc.E09-01-0080 Furuse, 1998, Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin, J Cell Biol, 141, 1539, 10.1083/jcb.141.7.1539 Furuse, 1998, A single gene product, claudin-1 or -2, reconstitutes tight junction strands and recruits occludin in fibroblasts, J Cell Biol, 143, 391, 10.1083/jcb.143.2.391 Günzel, 2013, Claudins and the modulation of tight junction permeability, Physiol Rev, 93, 525, 10.1152/physrev.00019.2012 Goncalves, 2013, Regulation of claudins in blood–tissue barriers under physiological and pathological states, Tissue Barriers, 1, e24782, 10.4161/tisb.24782 Krause, 2007, Structure and function of claudins, Biochim Biophys Acta, 1778, 631 Wolburg, 2003, Localization of claudin-3 in tight junctions of the blood–brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme, Acta Neuropathol (Berl), 105, 586, 10.1007/s00401-003-0688-z Nitta, 2003, Size-selective loosening of the blood–brain barrier in claudin-5-deficient mice, J Cell Biol, 161, 653, 10.1083/jcb.200302070 Daneman, 2010, The mouse blood–brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells, PLoS ONE, 5, 10.1371/journal.pone.0013741 Pfeiffer, 2011, Claudin-1 induced sealing of blood–brain barrier tight junctions ameliorates chronic experimental autoimmune encephalomyelitis, Acta Neuropathol (Berl), 122, 601, 10.1007/s00401-011-0883-2 Kooij, 2014, Disturbed function of the blood–cerebrospinal fluid barrier aggravates neuro-inflammation, Acta Neuropathol, 128, 267, 10.1007/s00401-013-1227-1 Suzuki, 2014, Crystal structure of a claudin provides insight into the architecture of tight junctions, Science, 344, 304, 10.1126/science.1248571 Dabrowski, 2015, Redox-sensitive structure and function of the first extracellular loop of the cell–cell contact protein claudin-1 – lessons from molecular structure to animal, Antioxid Redox Signal, 22, 1, 10.1089/ars.2013.5706 Coisne, 2005, Mouse syngenic in vitro blood–brain barrier model: a new tool to examine inflammatory events in cerebral endothelium, Lab Invest, 85, 734, 10.1038/labinvest.3700281 Hamm, 2004, Astrocyte mediated modulation of blood–brain barrier permeability does not correlate with a loss of tight junction proteins from the cellular contacts, Cell Tissue Res, 315, 157, 10.1007/s00441-003-0825-y Weksler, 2005, Blood–brain barrier-specific properties of a human adult brain endothelial cell line, FASEB J, 19, 1872, 10.1096/fj.04-3458fje Fletcher, 2012, Hepatitis C virus infects the endothelial cells of the blood–brain barrier, Gastroenterology, 142, 10.1053/j.gastro.2011.11.028 Willis, 2013, Partial recovery of the damaged rat blood–brain barrier is mediated by adherens junction complexes. extracellular matrix remodeling and macrophage infiltration following focal astrocyte loss, Neuroscience, 250, 773, 10.1016/j.neuroscience.2013.06.061 Chen, 2012, Ischemia-reperfusion impairs blood–brain barrier function and alters tight junction protein expression in the ovine fetus, Neuroscience, 226, 89, 10.1016/j.neuroscience.2012.08.043 Furuse, 2002, Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice, J Cell Biol, 156, 1099, 10.1083/jcb.200110122 Inai, 1999, Claudin-1 contributes to the epithelial barrier function in MDCK cells, Eur J Cell Biol, 78, 849, 10.1016/S0171-9335(99)80086-7 McCarthy, 2000, Inducible expression of claudin-1-myc but not occludin-VSV-G results in aberrant tight junction strand formation in MDCK cells, J Cell Sci, 113, 3387, 10.1242/jcs.113.19.3387 French, 2009, PKC and PKA phosphorylation affect the subcellular localization of claudin-1 in melanoma cells, Int J Med Sci, 6, 93, 10.7150/ijms.6.93 Fujibe, 2004, Thr(203) of claudin-1, a putative phosphorylation site for MAP kinase, is required to promote the barrier function of tight junctions, Exp Cell Res, 295, 36, 10.1016/j.yexcr.2003.12.014 Nunbhakdi-Craig, 2002, Protein phosphatase 2A associates with and regulates atypical PKC and the epithelial tight junction complex, J Cell Biol, 158, 967, 10.1083/jcb.200206114 Ishizaki, 2003, Cyclic AMP induces phosphorylation of claudin-5 immunoprecipitates and expression of claudin-5 gene in blood–brain-barrier endothelial cells via protein kinase A-dependent and -independent pathways, Exp Cell Res, 290, 275, 10.1016/S0014-4827(03)00354-9 Ahmad, 2011, Claudin-1 required for HCV virus entry has high potential for phosphorylation and O-glycosylation, Virol J, 8, 10.1186/1743-422X-8-229 Lynch, 2007, Cholesterol depletion alters detergent-specific solubility profiles of selected tight junction proteins and the phosphorylation of occludin, Exp Cell Res, 313, 2597, 10.1016/j.yexcr.2007.05.009 Price, 2005, The alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor trafficking regulator “stargazin” is related to the claudin family of proteins by its ability to mediate cell–cell adhesion, J Biol Chem, 280, 19711, 10.1074/jbc.M500623200 Takahashi, 2009, The E3 ubiquitin ligase LNX1p80 promotes the removal of claudins from tight junctions in MDCK cells, J Cell Sci, 122, 985, 10.1242/jcs.040055 Sadowska, 2010, Maternal glucocorticoid exposure alters tight junction protein expression in the brain of fetal sheep, Am J Physiol Heart Circ Physiol, 298, H179, 10.1152/ajpheart.00828.2009 D'Souza, 2009, Age-related changes of claudin expression in mouse liver, kidney, and pancreas, J Gerontol A: Biol Sci Med Sci, 64, 1146, 10.1093/gerona/glp118 Buttmann, 2007, Atorvastatin partially prevents an inflammatory barrier breakdown of cultured human brain endothelial cells at a pharmacologically relevant concentration, J Neurochem, 102, 1001, 10.1111/j.1471-4159.2007.04563.x Mahajan, 2008, Methamphetamine alters blood brain barrier permeability via the modulation of tight junction expression: implication for HIV-1 neuropathogenesis in the context of drug abuse, Brain Res, 1203, 133, 10.1016/j.brainres.2008.01.093 Perriere, 2007, A functional in vitro model of rat blood–brain barrier for molecular analysis of efflux transporters, Brain Res, 1150, 1, 10.1016/j.brainres.2007.02.091 Schrade, 2012, Expression and localization of claudins-3 and -12 in transformed human brain endothelium, Fluids Barriers CNS, 9 Liebner, 2008, Wnt/beta-catenin signaling controls development of the blood–brain barrier, J Cell Biol, 183, 409, 10.1083/jcb.200806024 Milatz, 2010, Claudin-3 acts as a sealing component of the tight junction for ions of either charge and uncharged solutes, Biochim Biophys Acta Biomembr, 1798, 2048, 10.1016/j.bbamem.2010.07.014 Hashimoto, 2008, Oxidative stress induces gastric epithelial permeability through claudin-3, Biochem Biophys Res Commun, 376, 154, 10.1016/j.bbrc.2008.08.140 Kobayashi, 2011, Distinct behavior of claudin-3 and -4 around lactation period in mammary alveolus in mice, Histochem Cell Biol, 136, 587, 10.1007/s00418-011-0863-6 Furuse, 1999, Manner of interaction of heterogeneous claudin species within and between tight junction strands, J Cell Biol, 147, 891, 10.1083/jcb.147.4.891 D'Souza, 2005, Phosphorylation of claudin-3 at threonine 192 by cAMP-dependent protein kinase regulates tight junction barrier function in ovarian cancer cells, J Biol Chem, 280, 26233, 10.1074/jbc.M502003200 Butt, 2012, Role of post translational modifications and novel crosstalk between phosphorylation and O-beta-GlcNAc modifications in human claudin-1, -3 and-4, Mol Biol Rep, 39, 1359, 10.1007/s11033-011-0870-7 Ito, 2011, Quantitative membrane protein expression at the blood–brain barrier of adult and younger cynomolgus monkeys, J Pharm Sci, 100, 3939, 10.1002/jps.22487 Hoshi, 2013, Quantitative atlas of blood–brain barrier transporters, receptors, and tight junction proteins in rats and common marmoset, J Pharm Sci, 102, 3343, 10.1002/jps.23575 Uchida, 2011, Quantitative targeted absolute proteomics of human blood–brain barrier transporters and receptors, J Neurochem, 117, 333, 10.1111/j.1471-4159.2011.07208.x Morita, 1999, Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands, Proc Natl Acad Sci U S A, 96, 511, 10.1073/pnas.96.2.511 Ueno, 2007, Molecular anatomy of the brain endothelial barrier: an overview of the distributional features, Curr Med Chem, 14, 1199, 10.2174/092986707780597943 Luissint, 2012, Guanine nucleotide-binding protein G alpha i2: a new partner of claudin-5 that regulates tight junction integrity in human brain endothelial cells, J Cereb Blood Flow Metab, 32, 860, 10.1038/jcbfm.2011.202 Honda, 2006, Adrenomedullin improves the blood–brain barrier function through the expression of claudin-5, Cell Mol Neurobiol, 26, 109, 10.1007/s10571-006-9028-x Wen, 2004, Selective decrease in paracellular conductance of tight junctions: role of the first extracellular domain of claudin-5, Mol Cell Biol, 24, 8408, 10.1128/MCB.24.19.8408-8417.2004 Ek, 2006, Functional effectiveness of the blood brain barrier to small water-soluble molecules in developing and adult opossum (Monodelphis domestica), J Comp Neurol, 496, 13, 10.1002/cne.20885 Mandel, 2012, The ubiquitin–proteasome pathway regulates claudin 5 degradation, J Cell Biochem, 113, 2415, 10.1002/jcb.24118 Soma, 2004, Thr(207) of claudin-5 is involved in size-selective loosening of the endothelial barrier by cyclic AMP, Exp Cell Res, 300, 202, 10.1016/j.yexcr.2004.07.012 Watabe, 2003, TGF-beta receptor kinase inhibitor enhances growth and integrity of embryonic stem cell-derived endothelial cells, J Cell Biol, 163, 1303, 10.1083/jcb.200305147 Taddei, 2008, Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5, Nat Cell Biol, 10, 923, 10.1038/ncb1752 Felinski, 2008, Glucocorticoids induce transactivation of tight junction genes occludin and claudin-5 in retinal endothelial cells via a novel cis-element, Exp Eye Res, 86, 867, 10.1016/j.exer.2008.01.002 Förster, 2006, Glucocorticoid effects on mouse microvascular endothelial barrier permeability are brain specific, J Physiol Lond, 573, 413, 10.1113/jphysiol.2006.106385 Burek, 2010, Claudin-5 as a novel estrogen target in vascular endothelium, Arterioscler Thromb Vasc Biol, 30, 10.1161/ATVBAHA.109.197582 Kanoski, 2010, The effects of a high-energy diet on hippocampal function and blood–brain barrier integrity in the rat, J Alzheimers Dis, 21, 207, 10.3233/JAD-2010-091414 Belanger, 2007, Hyperammonemia induces transport of taurine and creatine and suppresses claudin-12 gene expression in brain capillary endothelial cells in vitro, Neurochem Int, 50, 95, 10.1016/j.neuint.2006.07.005 Paganelli, 2011, Neonatal ichthyosis and sclerosing cholangitis syndrome: extremely variable liver disease severity from claudin-1 deficiency, J Pediatr Gastroenterol Nutr, 53, 350, 10.1097/MPG.0b013e3182169433 Katahira, 1997, Clostridium perfringens enterotoxin utilizes two structurally related membrane proteins as functional receptors in vivo, J Biol Chem, 272, 26652, 10.1074/jbc.272.42.26652 Hewitt, 2006, The claudin gene family: expression in normal and neoplastic tissues, BMC Cancer, 6, 10.1186/1471-2407-6-186 Kratzer, 2012, Complexity and developmental changes in the expression pattern of claudins at the blood–CSF barrier, Histochem Cell Biol, 138, 861, 10.1007/s00418-012-1001-9 Sirotkin, 1997, Identification, characterization, and precise mapping of a human gene encoding a novel membrane-spanning protein from the 22q11 region deleted in velo-cardio-facial syndrome, Genomics, 42, 245, 10.1006/geno.1997.4734 Uchida, 2013, Fluids Barriers CNS, 10, 21, 10.1186/2045-8118-10-21 Piehl, 2010, Participation of the second extracellular loop of claudin-5 in paracellular tightening against ions, small and large molecules, Cell Mol Life Sci, 67, 2131, 10.1007/s00018-010-0332-8 Zhang, 2010, Establishment of a neuroepithelial barrier by claudin5a is essential for zebrafish brain ventricular lumen expansion, Proc Natl Acad Sci U S A, 107, 1425, 10.1073/pnas.0911996107 Fujita, 2008, Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca(2+) absorption between enterocytes, Mol Biol Cell, 19, 1912, 10.1091/mbc.E07-09-0973 Bellmann, 2014, Highly conserved cysteines are involved in the oligomerization of occludin-redox dependency of the second extracellular loop, Antioxid Redox Signal, 20, 855, 10.1089/ars.2013.5288 Saitou, 1997, Mammalian occludin in epithelial cells: its expression and subcellular distribution, Eur J Cell Biol, 73, 222 Hirase, 1997, Occludin as a possible determinant of tight junction permeability in endothelial cells, J Cell Sci, 110, 1603, 10.1242/jcs.110.14.1603 Hwang, 2013, Tissue-specific expression of occludin, zona occludens-1, and junction adhesion molecule A in the duodenum, ielum, colon, kidney, liver, lung, brain, and skeletal muscle of C57Bl mice, J Physiol Pharmacol, 64, 11 Reijerkerk, 2006, Diapedesis of monocytes is associated with MMP-mediated occludin disappearance in brain endothelial cells, FASEB J, 20, 2550, 10.1096/fj.06-6099fje Savettieri, 2000, Neurons and ECM regulate occludin localization in brain endothelial cells, Neuroreport, 11, 1081, 10.1097/00001756-200004070-00035 Urich, 2012, Transcriptional profiling of human brain endothelial cells reveals key properties crucial for predictive in vitro blood–brain barrier models, PLOS ONE, 7, 10.1371/journal.pone.0038149 Hori, 2004, A pericyte-derived angiopoietin-1 multimeric complex induces occludin gene expression in brain capillary endothelial cells through Tie-2 activation in vitro, J Neurochem, 89, 503, 10.1111/j.1471-4159.2004.02343.x Kim, 2010, Role of PKC beta II and PKC delta in blood–brain barrier permeability during aglycemic hypoxia, Neurosci Lett, 468, 254, 10.1016/j.neulet.2009.11.007 Watanabe, 2013, Paracellular barrier and tight junction protein expression in the immortalized brain endothelial cell lines bEND.3, bEND.5 and mouse brain endothelial cell 4, Biol Pharm Bull, 36, 492, 10.1248/bpb.b12-00915 Saitou, 2000, Complex phenotype of mice lacking occludin, a component of tight junction strands, Mol Biol Cell, 11, 4131, 10.1091/mbc.11.12.4131 Ikenouchi, 2008, Loss of occludin affects tricellular localization of tricellulin, Mol Biol Cell, 19, 4687, 10.1091/mbc.E08-05-0530 Van Itallie, 2010, Occludin is required for cytokine-induced regulation of tight junction barriers, J Cell Sci, 123, 2844, 10.1242/jcs.065581 Buschmann, 2013, Occludin OCEL-domain interactions are required for maintenance and regulation of the tight junction barrier to macromolecular flux, Mol Biol Cell, 24, 3056, 10.1091/mbc.E12-09-0688 Titchenell, 2012, Novel atypical PKC inhibitors prevent vascular endothelial growth factor-induced blood–retinal barrier dysfunction, Biochem J, 446, 455, 10.1042/BJ20111961 Muthusamy, 2014, Ischemia-reperfusion injury induces occludin phosphorylation/ubiquitination and retinal vascular permeability in a VEGFR-2-dependent manner, J Cereb Blood Flow Metab, 34, 522, 10.1038/jcbfm.2013.230 Won, 2014, Progesterone attenuates hemorrhagic transformation after delayed tPA treatment in an experimental model of stroke in rats: involvement of the VEGF–MMP pathway, J Cereb Blood Flow Metab, 34, 72, 10.1038/jcbfm.2013.163 Chen, 2011, Occludin is regulated by epidermal growth factor receptor activation in brain endothelial cells and brains of mice with acute liver failure, Hepatology, 53, 1294, 10.1002/hep.24161 Ishihara, 2008, Endothelial cell barrier impairment induced by glioblastomas and transforming growth factor beta(2) involves matrix metalloproteinases and tight junction proteins, J Neuropathol Exp Neurol, 67, 435, 10.1097/NEN.0b013e31816fd622 Kebir, 2007, Human T(H)17 lymphocytes promote blood–brain barrier disruption and central nervous system inflammation, Nat Med, 13, 1173, 10.1038/nm1651 Li, 2005, Structure of the conserved cytoplasmic C-terminal domain of occludin: identification of the ZO-1 binding surface, J Mol Biol, 352, 151, 10.1016/j.jmb.2005.07.017 Tash, 2012, The occludin and ZO-1 complex, defined by small angle X-ray scattering and NMR, has implications for modulating tight junction permeability, Proc Natl Acad Sci U S A, 109, 10855, 10.1073/pnas.1121390109 Müller, 2005, The tight junction protein occludin and the adherens junction protein alpha-catenin share a common interaction mechanism with ZO-1, J Biol Chem, 280, 3747, 10.1074/jbc.M411365200 Nusrat, 2000, The coiled-coil domain of occludin can act to organize structural and functional elements of the epithelial tight junction, J Biol Chem, 275, 29816, 10.1074/jbc.M002450200 Raikwar, 2010, Nedd4-2 interacts with occludin to inhibit tight junction formation and enhance paracellular conductance in collecting duct epithelia, Am J Physiol Renal Physiol, 299, F436, 10.1152/ajprenal.00674.2009 Traweger, 2002, The tight junction-specific protein occludin is a functional target of the E3 ubiquitin-protein ligase itch, J Biol Chem, 277, 10201, 10.1074/jbc.M111384200 Ramirez, 2013, Inhibition of glycogen synthase kinase 3 beta promotes tight junction stability in brain endothelial cells by half-life extension of occludin and claudin-5, PLOS ONE, 8, 10.1371/journal.pone.0055972 Bauer, 2010, Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement, J Cereb Blood Flow Metab, 30, 837, 10.1038/jcbfm.2009.248 Lischper, 2010, Metalloproteinase mediated occludin cleavage in the cerebral microcapillary endothelium under pathological conditions, Brain Res, 1326, 114, 10.1016/j.brainres.2010.02.054 Masuda, 2011, LSR defines cell corners for tricellular tight junction formation in epithelial cells, J Cell Sci, 124, 548, 10.1242/jcs.072058 Higashi, 2013, Analysis of the ‘angulin’ proteins LSR, ILDR1 and ILDR2-tricellulin recruitment, epithelial barrier function and implication in deafness pathogenesis, J Cell Sci, 126, 966, 10.1242/jcs.116442 Olsen, 2006, Global, in vivo, and site-specific phosphorylation dynamics in signaling networks, Cell, 127, 635, 10.1016/j.cell.2006.09.026 Dörfel, 2013, CK2-dependent phosphorylation of occludin regulates the interaction with ZO-proteins and tight junction integrity, Cell Commun Signal, 11, 10.1186/1478-811X-11-40 Dörfel, 2012, Modulation of tight junction structure and function by kinases and phosphatases targeting occludin, J Biomed Biotechnol, 10.1155/2012/807356 Mun-Bryce, 1998, Matrix metalloproteinases in cerebrovascular disease, J Cereb Blood Flow Metab, 18, 1163, 10.1097/00004647-199811000-00001 Liu, 2012, Matrix metalloproteinase-2-mediated occludin degradation and caveolin-1-mediated claudin-5 redistribution contribute to blood–brain barrier damage in early ischemic stroke stage, J Neurosci, 32, 3044, 10.1523/JNEUROSCI.6409-11.2012 Blasig, 2011, Occludin protein family: oxidative stress and reducing conditions, Antioxid Redox Signal, 15, 1195, 10.1089/ars.2010.3542 Elali, 2012, Receptor activation enhances blood–brain barrier integrity in the ischemic brain and increases the abundance of ATP-binding cassette transporters ABCB1 and ABCC1 on brain capillary cells, Brain Pathol, 22, 175, 10.1111/j.1750-3639.2011.00517.x