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1 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: averin1{at}jhmi.edu.
Crosstalk between the actin cytoskeleton and the microtubule (MT) network plays a critical role in regulation of endothelial permeability. We have previously demonstrated that MT disruption by nocodazole results in increases in myosin light chain (MLC) phosphorylation, actomyosin contraction, cell retraction, and paracellular gap formation, cardinal features of endothelial barrier dysfunction [Verin et al., 2001, AJP LCMP, 281:3, L565-74; Birukova et al., 2004, J Cell Physiol, in press]. Although activation of cAMP-dependent protein kinase (PKA) opposes the barrier-disrupting effects of edemagenic agents on confluent EC monolayers, information about the molecular mechanisms of PKA-mediated endothelial cell (EC) barrier protection is limited. Our results suggest that microtubule disassembly alters neither intracellular cAMP levels nor PKA enzymatic activity, however, elevation of cAMP levels and PKA activation by either cholera toxin (1 µg/ml) or forskolin (50 µM) dramatically attenuates the decline in transendothelial electrical resistance induced by nocodazole in human pulmonary EC. Barrier-protective effects of PKA on EC were associated with PKA-mediated inhibition of nocodazole-induced stress fiber formation, Rho activation, phosphorylation of myosin phosphatase regulatory subunit at Thr696, and decreased MLC phosphorylation. In addition, forskolin pretreatment attenuated MT disassembly induced by nocodazole (0.2 µM). These results suggest a critical role for PKA activity in stabilization of the microtubule cytoskeleton, and provide a novel mechanism for cAMP-mediated regulation of Rho-induced actin cytoskeletal remodeling, actomyosin contraction and EC barrier dysfunction induced by microtubule disassembly.
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