| Claudin‑5 is a tetraspanin integral membrane protein belonging to the claudin family of tight‑junction components that forms selective paracellular barriers in endothelial and epithelial tissues, with particularly high expression in the brain microvasculature and lung. Claudin‑5 contains four membrane‑spanning domains and two extracellular loops that form continuous sealing strands between adjacent cells, and its short intracellular termini interact with tight‑junction plaque proteins such as ZO‑1 to couple the junction to the actin cytoskeleton and stabilize cell‑cell contact. Claudin‑5 is the most enriched claudin isoform and functions as a size‑selective molecular sieve that tightly restricts paracellular flux of small hydrophilic molecules and ions, thereby maintaining central nervous system homeostasis while limiting CNS penetration of many small‑molecule therapeutics. Claudin‑5 levels are actively regulated by growth and inflammatory signals, and its downregulation or junctional remodeling in neuroinflammatory and neurodegenerative settings increases permeability and facilitates immune and humoral access, whereas reinforcement of Claudin‑5 expression in brain endothelial cells reduces paracellular leak and can attenuate lung cancer cell invasion across the endothelium, implicating Claudin‑5‑dependent barrier integrity in the control of brain metastasis. Altered Claudin‑5 expression correlates with grade, stage, and metastatic propensity in multiple carcinomas, and both loss and overexpression have been associated with poor prognosis depending on tissue context. |
Lane 1: HUVEC, Lane 2: Mouse lung
