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Signals Modulating p‐Glycoprotein Activity in Brain Capillaries
Author(s) -
Miller David S.,
Hartz Anika M.S.,
Bauer Bjoern
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a874-d
Subject(s) - autocrine signalling , microbiology and biotechnology , signal transduction , paracrine signalling , p glycoprotein , receptor , biology , blood–brain barrier , extracellular , chemistry , pharmacology , biochemistry , endocrinology , central nervous system , multiple drug resistance , antibiotics
At the blood‐brain barrier, p‐glycoprotein, an ATP‐driven efflux pump, limits drug entry into the brain and thus CNS pharmacotherapy. We have identified multiple extracellular and intracellular signals that regulate this transporter. Eight signaling pathways have been defined and partially mapped. Three pathways are triggered by elements of the brain’s innate immune response, one by reactive oxygen species, one by glutamate, one by drug‐nuclear receptor (PXR) interactions and two by elevated beta‐amyloid levels. Three work over the short‐term (minutes) to reduce transport function with no change in transporter expression. Five work over the long‐term (hours to days). Of these, four increase both function and expression and one decreases function and expression. Signaling is complex, with several pathways having common signaling elements (TNF‐R1, ET‐B receptor, protein kinase C, NO synthase), suggesting a regulatory network. Several pathways utilize autocrine/paracrine elements, involving release of the pro‐inflammatory cytokine, TNF‐alpha, and the polypeptide hormone, endothelin. Finally, several steps in signaling are potential therapeutic targets that could be used to modulate p‐glycoprotein activity.