Fig. 3
From: The CLDN5 gene at the blood-brain barrier in health and disease
The TJ proteins mediated CLDN5 regulation in the brain endothelial cells
(a) VE-cadherin-mediated CLDN5 regulation via PI3K/Akt signaling. The trans-interaction of VE-cadherin activates PI3K/Akt signaling and leads Rac1-mediated junctional stabilization and inhibits β-catenin/FoxO1-mediated CLDN5 suppression. (b) JAM-A-mediated CLDN5 regulation via cAMP signaling. The trans-interactions of JAM-A enhances cAMP level and leads protein kinase A (PKA)-dependent barrier stabilization via Rac1 activation and PKA-independent CLDN5 up-regulation via C-EBP-α. (c) ZO-1-mediated CLDN5 regulation by preventing non-junctional RhoA activation. Well-stabilized ZO-1 prevents the translocalization of ZO-1-associated nucleic acid binding protein (ZONAB) to the nucleus by direct interaction and by inhibiting non-junctional GEF-H1 activation via paracingulin. RhoA activation induces cell contraction by accumulated phosphorylated myosin light chain (MLC). Nitric oxidase (NO) and cAMP signaling inhibits cell contraction, but calcium signaling promotes it. CaM, calmodulin; CaMK, calmodulin kinase; C/EBP-α, CCAAT/enhancer-binding protein-α; eNOS, endothelial nitric oxide synthase; EPAC, exchange proteins directly activated by cAMP; GSK-3β, glycogen synthase kinase-3β; MLC, myosin light chain; MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; PI3K, phosphoinositide 3-kinases; PKA, protein kinase A; PKG, protein kinase G