Regulation of beta-Adrenergic Receptor Trafficking and Lung Microvascular Endothelial Cell Permeability by Rab5 GTPase

Rab5 GTPase modulates the trafficking of the cell surface receptors, including G protein-coupled beta-adrenergic receptors (beta-ARs). Here, we have determined the role of Rab5 in regulating the internalization of beta-ARs in lung microvascular endothelial cells (LMECs) and in maintaining the integrity and permeability of endothelial cell barrier. Our data demonstrate that lipopolysaccharide (LPS) treatment disrupts LMEC barrier function and reduces the cell surface expression of beta-ARs. Furthermore, the activation of beta-ARs, particularly beta 2-AR, is able to protect the LMEC permeability from LPS injury. Moreover, siRNA-mediated knockdown of Rab5 inhibits both the basal and agonist- provoked internalization of beta-ARs, therefore, enhancing the cell surface expression of the receptors and receptor-mediated ERK1/2 activation. Importantly, knockdown of Rab5 not only inhibits the LPS-induced effects on beta-ARs but also protects the LMEC monolayer permeability. All together, these data provide strong evidence indicating a crucial role of Rab5-mediated internalization of beta-ARs in functional regulation of LMECs.