| Rapid loss of blood-brain barrier P-glycoprotein activity through transporter internalization demonstrated using a novel in situ proteolysis protection assay. | |
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MedLine Citation:
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PMID: 20628400 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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-alpha acting via protein kinase C (PKC)beta1. 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 PKCbeta1 did not protect P-glycoprotein. Thus, VEGF and PKCbeta1 reduce P-glycoprotein activity by distinct mechanisms. |
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Authors:
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Brian T Hawkins; Robert R Rigor; David S Miller |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Intramural Date: 2010-07-14 |
Journal Detail:
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Title: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism Volume: 30 ISSN: 1559-7016 ISO Abbreviation: J. Cereb. Blood Flow Metab. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-09-02 Completed Date: 2010-10-19 Revised Date: 2011-09-13 |
Medline Journal Info:
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Nlm Unique ID: 8112566 Medline TA: J Cereb Blood Flow Metab Country: United States |
Other Details:
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Languages: eng Pagination: 1593-7 Citation Subset: IM |
Affiliation:
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Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blood-Brain Barrier / drug effects*, metabolism* Blotting, Western Capillaries / drug effects Cerebrovascular Circulation / drug effects Endocytosis / drug effects Endopeptidase K / pharmacology* Enzyme Activation / drug effects Injections, Intraventricular Male Membrane Proteins / metabolism Neuroprotective Agents* P-Glycoprotein / metabolism* Phorbol Esters / pharmacology Rats Rats, Sprague-Dawley Vascular Endothelial Growth Factor A / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Membrane Proteins; 0/Neuroprotective Agents; 0/P-Glycoprotein; 0/Phorbol Esters; 0/Vascular Endothelial Growth Factor A; 54662-30-5/12-deoxyphorbolphenylacetate-20-acetate; EC 3.4.21.64/Endopeptidase K |
| Comments/Corrections | |
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