Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 30, Issue 9, Pages 1593-1597Publisher
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2010.117
Keywords
blood-brain barrier; endothelium; pharmacology; physiology; vascular biology
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Funding
- National Institutes of Health, National Institute of Environmental Health Sciences
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Blood-brain barrier (BBB) P-glycoprotein activity is rapidly reduced by vascular endothelial growth factor (VEGF) acting via Src and by tumor necrosis factor-a acting via protein kinase C (PKC)beta 1. To probe underlying mechanism(s), we developed an in vivo, immunoblot-based proteinase K (PK) protection assay to assess the changes in the P-glycoprotein content of the BBB's luminal membrane. Infusion of PK into the brain vasculature selectively cleaved luminal membrane P-glycoprotein, leaving intracellular proteins intact. Intracerebroventricular injection of VEGF partially protected P-glycoprotein from proteolytic cleavage, consistent with transporter internalization. Activation of PKC beta 1 did not protect P-glycoprotein. Thus, VEGF and PKC beta 1 reduce P-glycoprotein activity by distinct mechanisms. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 1593-1597; doi:10.1038/jcbfm.2010.117; published online 14 July 2010
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