Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 46, Pages 33324-33334Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.483487
Keywords
Actin; Brain; Cytoskeleton; Endocytosis; Endothelium; Tight Junctions; Methamphetamine; Arp2; 3 Complex; Actin; Nucleation; Blood-Brain Barrier; Occludin; Endocytosis; Endo
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Funding
- National Institutes of Health [DA027569, MH072567, MH098891, MH063022]
- Miami Center for AIDS Research at the University of Miami [P30AI073961]
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Background: Methamphetamine is a drug of abuse that disrupts the blood-brain barrier. Results: Blocking actin nucleation protects against methamphetamine-induced occludin internalization and disruption of blood-brain barrier integrity. Conclusion: Methamphetamine-induced transendothelial breaches may result from actin-mediated redistribution of occludin. Significance: Actin cytoskeletal dynamics modulates redistribution of occludin and blood-brain barrier integrity. Methamphetamine (METH) is a drug of abuse with neurotoxic and neuroinflammatory effects, which include disruption of the blood-brain barrier (BBB) and alterations of tight junction protein expression. This study focused on the actin cytoskeletal rearrangement as a modulator of METH-induced redistribution of tight junction protein occludin in brain endothelial cells. Exposure to METH resulted in a shift of occludin localization from plasma membranes to endosomes. These changes were accompanied by activation of the actin-related protein 2/3 (Arp2/3) complex, which stimulates actin polymerization by promoting actin nucleation. In addition, METH-induced coronin-1b phosphorylation diminishes the inhibitory effect of nonphosphorylated coronin-1b on actin nucleation. Blocking actin nucleation with CK-666, a specific inhibitor of the Arp2/3 complex, protected against METH-induced occludin internalization and increased transendothelial monocyte migration. Importantly, treatment with CK-666 attenuated a decrease in occludin levels in brain microvessels and BBB permeability of METH-injected mice. These findings indicate that actin cytoskeletal dynamics is detrimental to METH-induced BBB dysfunction by increasing internalization of occludin.
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